Nitrogen-containing heterocyclic derivatives, medicinal compositions containing the same and medicinal use thereof

ABSTRACT

The present invention provides nitrogen-containing heterocyclic derivatives represented by the general formula: 
                         
wherein X 1  represents N or CR 1 ; X 2  represents N or CR 2 ; X 3  represents N or CR 3 ; X 4  represents N or CR 4 ; and with the proviso that one or two of X 1  to X 4  represent N; R represents optionally substituted C 3-8  cycloalkyl, optionally substituted C 6-10  aryl, etc.; R 1  to R 4  represent H, a halogen atom, etc.) or pharmaceutically acceptable salts thereof, or prodrugs thereof, which exert an excellent inhibitory activity in human SGLT2 and are useful as agents for the prevention or treatment of a disease associated with hyperglycemia such as diabetes, diabetic complications, obesity or the like, pharmaceutical compositions comprising the same, and medicinal uses thereof.

TECHNICAL FIELD

The present invention relates to nitrogen-containing heterocyclicderivatives or pharmaceutically acceptable salts thereof, or prodrugsthereof which are useful as medicaments, pharmaceutical compositionscomprising the same and pharmaceutical uses thereof.

More particularly, the present invention relates to nitrogen-containingheterocyclic derivatives or pharmaceutically acceptable salts thereof,or prodrugs thereof which exhibit an inhibitory activity inhuman SGLT2and are useful as agents for the prevention or treatment of a diseaseassociated with hyperglycemia such as diabetes, diabetic complications,obesity or the like, pharmaceutical compositions comprising the same,and pharmaceutical uses thereof.

BACKGROUND ART

Diabetes is one of lifestyle-related diseases with the background ofchange of eating habit and lack of exercise. Hence, diet and exercisetherapies are performed in patients with diabetes. Furthermore, when itssufficient control and continuous performance are difficult, drugtreatment is simultaneously performed. Now, biguanides, sulfonylureas,insulin sensitivity enhancers and the like have been employed asantidiabetic agents. However, biguanides and sulfonylureas showoccasionally adverse effects such as lactic acidosis and hypoglycemia,respectively. Insulin sensitivity enhancers show occasionally adverseeffects such as edema, and are concerned for advancing obesity.Therefore, in order to solve these problems, it has been desired todevelop antidiabetic agents having a new mechanism.

In recent years, research and development of new type antidiabeticagents have been progressing, which promote urinary glucose excretionand lower blood glucose level by preventing reabsorption of excessglucose at the kidney (for example, see the following Reference 1). Inaddition, it is reported that SGLT2 (Na⁺/glucose cotransporter 2) ispresent in the S1 segment of the kidney's proximal tubule andparticipates mainly in reabsorption of glucose filtrated throughglomerular (for example, see the following Reference 2). Accordingly,inhibiting a human SGLT2 activity prevents reabsorption of excessglucose at the kidney, subsequently promotes excreting excess glucosethough the urine, and normalizes blood glucose level. Therefore, fastdevelopment of antidiabetic agents which have a potent inhibitoryactivity in human SGLT2 and have a new mechanism has been desired. Inaddition, since such agents for promoting the excretion of urinaryglucose excrete excess glucose though the urine and consequently theglucose accumulation in the body is decreased, they are also expected tohave a preventing or alleviating effect on obesity and a diureticeffect. Furthermore, the agents are considered to be useful for variousrelated diseases which occur accompanying the progress of diabetes orobesity due to hyperglycemia.

Reference 1: Luciano Rossetti, and other 4 persons, J. Clin. Invest.,May 1987, Vol. 79, pp. 1510-1515

Reference 2: Yoshikatsu Kanai, and other 4 persons, J. Clin. Invest.,January 1994, Vol. 93, pp. 397-404

DISCLOSURE OF THE INVENTION

The present inventors have studied earnestly to find compounds having aninhibitory activity in human SGLT2. As a result, it was found thatcompounds represented by the following general formula (I) show anexcellent inhibitory activity in human SGLT2, thereby forming the basisof the present invention.

The present invention is to provide the following nitrogen-containingheterocyclic derivatives or pharmaceutically acceptable salts thereof orprodrugs thereof which show an excellent hypoglycemic effect by exertingan inhibitory activity in human SGLT2 and excreting excess glucose inthe urine through preventing the reabsorption of glucose at the kidney,pharmaceutical compositions comprising the same, and pharmaceutical usesthereof and production intermediates thereof.

This is, the present invention relates to

[1] a nitrogen-containing heterocyclic derivative represented by thegeneral formula:

[wherein

-   X¹ represents N or CR¹;-   X² represents N or CR²;-   X³ represents N or CR³;-   X⁴ represents N or CR⁴;    and with the proviso that one or two of X¹, X², X³ and X⁴ represent    N;-   R represents a C₃₋₈ cycloalkyl group which may have the same or    different 1 to 3 groups selected from the following substituent    group (A), a C₆₋₁₀ aryl group which may have the same or different 1    to 3 groups selected from the following substituent group (B), a    C₂₋₉ heterocycloalkyl group which may have the same or different 1    to 3 groups selected from the following substituent group (A), or a    C₁₋₉ heteroaryl group which may have the same or different 1 to 3    groups selected from the following substituent group (B);-   R¹ to R⁴ are the same or different, independently represents a    hydrogen atom or a group selected from the following substituent    group (D);-   substituent group (A) consists of a halogen atom, a nitro group, a    cyano group, an oxo group, -G¹, —OG², —SG², —N(G²)₂, —C(═O)G²,    —C(═O)OG², —C(═O)N(G²)₂, —S(═O)₂G², —S(═O)₂OG², —S(═O)₂N(G²)₂,    —S(═O)G¹, —OC(═O)G¹, —OC(═O)N(G²)₂, —NHC(═O)G², —OS(═O)₂G¹,    —NHS(═O)₂G¹ and —C(═O)NHS(═O)₂G¹;-   substituent group(B) consists of a halogen atom, a nitro group, a    cyano group, -G¹, —OG², —SG², —N(G²)₂, -G³OG⁴, -G³N(G⁴)₂, —C(═O)G²,    —C(═O)OG², —C(═O)N(G²)₂, —S(═O)₂G², —S(═O)₂OG², —S(═O)₂N(G²)₂,    —S(═O)G¹, —OC(═O)G¹, —OC(═O)N(G²)₂, —NHC(═O)G², —OS(═O)₂G¹,    —NHS(═O)₂G¹ and —C(═O)NHS(═O)₂G¹-   (in the substituent group (A) and/or (B), G¹ represents a C₁₋₆ alkyl    group which may have the same or different 1 to 3 groups selected    from the following substituent group (C), a C₂₋₆ alkenyl group which    may have the same or different 1 to 3 groups selected from the    following substituent group (C), a C₂₋₆ alkynyl group which may have    the same or different 1 to 3 groups selected from the following    substituent group (C), a C₃₋₈ cycloalkyl group which may have the    same or different 1 to 3 groups selected from the following    substituent group (C), a C₆₋₁₀ aryl group which may have the same or    different 1 to 3 groups selected from the following substituent    group (D), a C₂₋₉ heterocycloalkyl group which may have the same or    different 1 to 3 groups selected from the following substituent    group (C), a C₁₋₉ heteroaryl group which may have the same or    different 1 to 3 groups selected from the following substituent    group (D);-   G²represents a hydrogen atom, a C₁₋₆ alkyl group which may have the    same or different 1 to 3 groups selected from the following    substituent group (C), a C₂₋₆ alkenyl group which may have the same    or different 1 to 3 groups selected from the following substituent    group (C), a C₂₋₆ alkynyl group which may have the same or different    1 to 3 groups selected from the following substituent group (C), a    C₃₋₈ cycloalkyl group which may have the same or different 1 to 3    groups selected from the following substituent group (C), a C₆₋₁₀    aryl group which may have the same or different 1 to 3 groups    selected from the following substituent group (D), a C₂₋₉    heterocycloalkyl group which may have the same or different 1 to 3    groups selected from the following substituent group (D), a C₁₋₉    heteroaryl group which may have the same or different 1 to 3 groups    selected from the following substituent group (D), and with the    proviso that G²are the same or different when there are more than    one G²in the substituents;-   G³ represents a C₁₋₆ alkyl group;-   G⁴ represents a C₁₋₆ alkyl group which may have the same or    different 1 to 3 groups selected from the following substituent    group (C), and with the proviso that G⁴are the same or different    when there are more than one G⁴ in the substituents;-   substituent group (C) consists of a halogen atom, a nitro group, a    cyano group, an oxo group, -G⁵, —OG⁶, —SG⁶, —N(G⁶)₂, —C(═O)G⁶,    —C(═O)OG⁶, —C(═O)N(G⁶)₂, —S(═O)₂G⁶, —S(═O)₂OG⁶, —S(═O)₂N(G⁶)₂,    —S(═O)G⁵, —OC(═O)G⁵, —OC(═O)N(G⁶)₂, —NHC(═O)G⁶, —OS(═O)₂G⁵,    —NHS(═O)₂G⁵ and —C(═O)NHS(═O)₂G⁵; and-   substituent group (D) consists of a halogen atom, a nitro group, a    cyano group, -G⁵, —OG⁶, —SG⁶, —N(G⁶)₂, —C(═O)G⁶, —C(═O)OG⁶,    —C(═O)N(G⁶)₂, —S(═O)₂G⁶, —S(═O)₂OG⁶, —S(═O)₂N(G⁶)₂, —S(═O)G⁵,    —OC(═O)G⁵, —OC(═O)N(G⁶)₂, —NHC(═O)G⁶, —OS(═O)₂G⁵, —NHS(═O)₂G⁵ and    —C(═O)NHS(═O)₂G⁵-   (in the substituent group (C) and/or (D), G⁵ represents a C₁₋₆ alkyl    group, a HO—C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₂₋₆ alkynyl    group, a C₃₋₈ cycloalkyl group, a C₆₋₁₀ aryl group, a C₂₋₉    heterocycloalkyl group or a C₁₋₉ heteroaryl group;-   G⁶represents a hydrogen atom, a C₁₋₆ alkyl group, a C₂₋₆ alkenyl    group, a C₂₋₆ alkynyl group, a C₃₋₈ cycloalkyl group, a C₆₋₁₀ aryl    group, a C₂₋₉ heterocycloalkyl group or a C₁₋₉ heteroaryl group, and    with the proviso that G⁶ are the same or different when there are    more than one G in the substituents))-   and with the proviso that when X¹ and X³ independently represent N    or CH;-   X² represents N or CR² (with the proviso that R² represents a    hydrogen atom, a halogen atom, a C₁₋₆alkyl group, a C₃₋₈cycloalkyl    group, —O—C₁₋₆ alkyl, an amino group, —NH—C₂₋₇ acyl, —NH—C₁₋₆ alkyl    or —N(C₁₋₆ alkyl)₂); and-   X⁴ represents N or CR⁴ (with the proviso that R⁴ represents a    hydrogen atom or a C₁₋₆ alkyl group), R represents the above-defined    group except for the following substituent:

-   (wherein Z represents a hydrogen atom, a halogen atom, a C₁₋₆ alkyl    group which may have a substituent selected from the following    substituent group (α), —O—C₁₋₆ alkyl which may have a substituent    selected from the following substituent group (β), —S—C₁₋₆ alkyl    which may have a substituent selected from the following substituent    group (β) or a C₃₋₈ cycloalkyl group; substituent group (α) consists    of a halogen atom, a hydroxy group and —O—C₁₋₆ alkyl; and-   substituent group (β) consists of a hydroxy group and —O—C₁₋₆    alkyl)] or a pharmaceutically acceptable salt thereof, or a prodrug    thereof;

[2] a nitrogen-containing heterocyclic derivative as described in theabove [1] wherein R represents a phenyl group which may have the same ordifferent 1 to 3 groups selected from the following substituent group(B), or a pharmaceutically acceptable salt thereof, or a prodrug thereof[wherein substituent group (B) consists of a halogen atom, a nitrogroup, a cyano group, -G¹, —OG², —SG², —N(G²)₂, -G³OG⁴, -G³N(G⁴)₂,—C(═O)G², —C(═O)OG², —C(═O)N(G²)₂, —S(═O)₂G², —S(═O)₂OG², —S(═O)₂N(G²)₂,—S(═O)G¹, —OC(═O)G¹, —OC(═O)N(G²)₂, —NHC(═O)G², —OS(═O)₂G¹, —NHS(═O)₂G¹and —C(═O)NHS(═O)₂G¹ (in the substituent group (B), G¹ represents a C₁₋₆alkyl group which may have the same or different 1 to 3 groups selectedfrom the following substituent group (C), a C₂₋₆ alkenyl group which mayhave the same or different 1 to 3 groups selected from the followingsubstituent group (C), a C₂₋₆ alkynyl group which may have the same ordifferent 1 to 3 groups selected from the following substituent group(C), a C₃₋₈ cycloalkyl group which may have the same or different 1 to 3groups selected from the following substituent group (C), a C₆₋₁₀ arylgroup which may have the same or different 1 to 3 groups selected fromthe following substituent group (D), a C₂₋₉ heterocycloalkyl group whichmay have the same or different 1 to 3 groups selected from the followingsubstituent group (C), a C₁₋₉ heteroaryl group which may have the sameor different 1 to 3 groups selected from the following substituent group(D);

-   G²represents a hydrogen atom, a C₁₋₆ alkyl group which may have the    same or different 1 to 3 groups selected from the following    substituent group (C), a C₂₋₆ alkenyl group which may have the same    or different 1 to 3 groups selected from the following substituent    group (C), a C₂₋₆ alkynyl group which may have the same or different    1 to 3 groups selected from the following substituent group (C), a    C₃₋₈ cycloalkyl group which may have the same or different 1 to 3    groups selected from the following substituent group (C), a C₆₋₁₀    aryl group which may have the same or different 1 to 3 groups    selected from the following substituent group (D), a C₂₋₉    heterocycloalkyl group which may have the same or different 1 to 3    groups selected from the following substituent group (D), a C₁₋₉    heteroaryl group which may have the same or different 1 to 3 groups    selected from the following substituent group (D), and with the    proviso that G²are the same or different when there are more than    one G²in the substituents; G³ represents a C₁₋₆ alkyl group;-   G⁴ represents a C₁₋₆ alkyl group which may have the same or    different 1 to 3 groups selected from the following substituent    group (C), and with the proviso that G⁴are the same or different    when there are more than one G⁴ in the substituents;-   substituent group (C) consists of a halogen atom, a nitro group, a    cyano group, an oxo group, -G⁵, —OG⁶, —SG⁶, —N(G⁶)₂, —C(═O)G⁶,    —C(═O)OG⁶, —C(═O)N(G⁶)₂, —S(═O)₂G⁶, —S(═O)₂OG⁶, —S(═O)₂N(G⁶)₂,    —S(═O)G⁵, —OC(═O)G⁵, —OC(═O)N(G⁶)₂, —NHC(═O)G⁶, —OS(═O)₂G⁵,    —NHS(═O)₂G⁵ and —C(═O)NHS(═O)₂G⁵; and-   substituent group (D) consists of a halogen atom, a nitro group, a    cyano group, -G⁵, —OG⁶, —SG⁶, —N(G⁶)₂, —C(═O)G⁶, —C(═O)OG⁶,    —C(═O)N(G⁶)₂, —S(═O)₂G⁶, —S(═O)₂OG⁶, —S(═O)₂N(G⁶)₂, —S(═O)G⁵,    —OC(═O)G⁵, —OC(═O)N(G⁶)₂, —NHC(═O)G⁶, —OS(═O)₂G⁵, —NHS(═O)₂G⁵and    —C(═O)NHS(═O)₂G⁵-   (in the substituent group (C) and/or (D), G⁵ represents a C₁₋₆ alkyl    group, a C₂₋₆ alkenyl group, a C₂₋₆ alkynyl group, a C₃₋₈ cycloalkyl    group, a C₆₋₁₀ aryl group, a C₂₋₉ heterocycloalkyl group or a C₁₋₉    heteroaryl group; and G⁶represents a hydrogen atom, a C₁₋₆ alkyl    group, a C₂₋₆ alkenyl group, a C₂₋₆ alkynyl group, a C₃₋₈ cycloalkyl    group, a C₆₋₁₀ aryl group, a C₂₋₉ heterocycloalkyl group or a C₁₋₉    heteroaryl group and with the proviso that G⁶ are the same or    different when there are more than one G⁶ in the substituents))];

[3] a pharmaceutical composition comprising as an active ingredient anitrogen-containing heterocyclic derivative as described in the above[1] or [2], or a pharmaceutically acceptable salt thereof, or a prodrugthereof;

[4] a pharmaceutical composition as described in the above [3] whereinthe composition is a human SGLT2 inhibitor;

[5] a pharmaceutical composition as described in the above [4 ] whereinthe composition is an agent for the prevention or treatment of a diseaseassociated with hyperglycemia;

[6] a pharmaceutical composition as described in the above [5] whereinthe disease associated with hyperglycemia is selected from the groupconsisting of diabetes, diabetic complications, obesity,hyperinsulinemia, glucose metabolism disorders, hyperlipidemia,hypercholesterolemia, hypertriglyceridemia, lipid metabolism disorders,atherosclerosis, hypertension, congestive heart failure, edema,hyperuricemia and gout;

[7] a pharmaceutical composition as described in the above [6] whereinthe disease associated with hyperglycemia is diabetes;

[8] a pharmaceutical composition as described in the above [6] whereinthe disease associated with hyperglycemia is diabetic complications;

[9] a pharmaceutical composition as described in the above [6] whereinthe disease associated with hyperglycemia is obesity;

[10] a method for the prevention or treatment of a disease associatedwith hyperglycemia, which comprises administering an effective amount ofa nitrogen-containing heterocyclic derivative as described in the above[1] or [2], or a pharmaceutically acceptable salt thereof, or a prodrugthereof;

[11] a use of a nitrogen-containing heterocyclic derivative as describedin the above [1] or [2], or a pharmaceutically acceptable salt thereof,or a prodrug thereof for the manufacture of a pharmaceutical compositionfor the prevention or treatment of a disease associated withhyperglycemia;

[12] a pharmaceutical combination which comprises (A) anitrogen-containing heterocyclic derivative as described in the above[1] or [2], or a pharmaceutically acceptable salt thereof, or a prodrugthereof, and (B) at least one member selected from the group consistingof an insulin sensitivity enhancer, a glucose absorption inhibitor, abiguanide, an insulin secretion enhancer, insulin or an insulinanalogue, a glucagon receptor antagonist, an insulin receptor kinasestimulant, a tripeptidyl peptidase II inhibitor, a dipeptidyl peptidaseIV inhibitor, a protein tyrosine phosphatase-1B inhibitor, a glycogenphosphorylase inhibitor, a glucose-6-phosphatase inhibitor, afructose-bisphosphatase inhibitor, a pyruvate dehydrogenase inhibitor, ahepatic gluconeogenesis inhibitor, D-chiroinsitol, a glycogen synthasekinase-3 inhibitor, glucagon-like peptide-1, a glucagon-like peptide-1analogue, a glucagon-like peptide-1 agonist, amylin, an amylin analogue,an amylin agonist, an aldose reductase inhibitor, an advanced glycationend products formation inhibitor, a protein kinase C inhibitor, aγ-aminobutyric acid receptor antagonist, a sodium channel antagonist, atranscript factor NF-κB inhibitor, a lipid peroxidase inhibitor, anN-acetylated-α-linked-acid-dipeptidase inhibitor, insulin-like growthfactor-I, platelet-derived growth factor, a platelet-derived growthfactor analogue, epidermal growth factor, nerve growth factor, acarnitine derivative, uridine, 5-hydroxy-1-methylhydantoin, EGB-761,bimoclomol, sulodexide, Y-128, a hydroxymethyl-glutaryl coenzyme Areductase inhibitor, a fibric acid derivative, a β₃-adrenoceptoragonist, an acyl-coenzyme A: cholesterol acyltransferase inhibitor,probcol, a thyroid hormone receptor agonist, a cholesterol absorptioninhibitor, a lipase inhibitor, a microsomal triglyceride transferprotein inhibitor, a lipoxygenase inhibitor, a carnitinepalmitoyl-transferase inhibitor, a squalene synthase inhibitor, alow-density lipoprotein receptor enhancer, a nicotinic acid derivative,a bile acid sequestrant, a sodium/bile acid cotransporter inhibitor, acholesterol ester transfer protein inhibitor, an appetite suppressant,an angiotensin-converting enzyme inhibitor, a neutral endopeptidaseinhibitor, an angiotensin II receptor antagonist, anendothelin-converting enzyme inhibitor, an endothelin receptorantagonist, a diuretic agent, a calcium antagonist, a vasodilatingantihypertensive agent, a sympathetic blocking agent, a centrally actingantihypertensive agent, an α₂-adrenoceptor agonist, an antiplateletsagent, a uric acid synthesis inhibitor, a uricosuric agent and a urinaryalkalinizer;

[13] a pharmaceutical combination as described in the above [12] for theprevention or treatment of a disease associated with hyperglycemia;

[14] a pharmaceutical combination as described in the above [13] whereina component (B) is at least one member selected from the groupconsisting of an insulin sensitivity enhancer, a glucose absorptioninhibitor, a biguanide, an insulin secretion enhancer, insulin or aninsulin analogue, a glucagon receptor antagonist, an insulin receptorkinase stimulant, a tripeptidyl peptidase II inhibitor, a dipeptidylpeptidase IV inhibitor, a protein tyrosine phosphatase-1B inhibitor, aglycogen phosphorylase inhibitor, a glucose-6-phosphatase inhibitor, afructose-bisphosphatase inhibitor, a pyruvate dehydrogenase inhibitor, ahepatic gluconeogenesis inhibitor, D-chiroinsitol, a glycogen synthasekinase-3 inhibitor, glucagon-like peptide-1, a glucagon-like peptide-1analogue, a glucagon-like peptide-1 agonist, amylin, an amylin analogue,an amylin agonist and an appetite suppressant, and the diseaseassociated with hyperglycemia is diabetes;

[15] a pharmaceutical combination as described in the above [14] whereina component (B) is at least one member selected from the groupconsisting of an insulin sensitivity enhancer, a glucose absorptioninhibitor, a biguanide, an insulin secretion enhancer, insulin or aninsulin analogue, a glucagon receptor antagonist, an insulin receptorkinase stimulant, a tripeptidyl peptidase II inhibitor, a dipeptidylpeptidase IV inhibitor, a protein tyrosine phosphatase-1B inhibitor, aglycogen phosphorylase inhibitor, a glucose-6-phosphatase inhibitor, afructose-bisphosphatase inhibitor, a pyruvate dehydrogenase inhibitor, ahepatic gluconeogenesis inhibitor, D-chiroinsitol, a glycogen synthasekinase-3 inhibitor, glucagon-like peptide-1, a glucagon-like peptide-1analogue, a glucagon-like peptide-1 agonist, amylin, an amylin analogueand an amylin agonist;

[16] a pharmaceutical combination as described in the above [15] whereina component (B) is at least one member selected from the groupconsisting of an insulin sensitivity enhancer, a glucose absorptioninhibitor, a biguanide, an insulin secretion enhancer and insulin or aninsulin analogue;

[17] a pharmaceutical combination as described in the above [13] whereina component (B) is at least one member selected from the groupconsisting of an insulin sensitivity enhancer, a glucose absorptioninhibitor, a biguanide, an insulin secretion enhancer, insulin or aninsulin analogue, a glucagon receptor antagonist, an insulin receptorkinase stimulant, a tripeptidyl peptidase II inhibitor, a dipeptidylpeptidase IV inhibitor, a protein tyrosine phosphatase-1B inhibitor, aglycogen phosphorylase inhibitor, a glucose-6-phosphatase inhibitor, afructose-bisphosphatase inhibitor, a pyruvate dehydrogenase inhibitor, ahepatic gluconeogenesis inhibitor, D-chiroinsitol, glycogen synthasekinase-3 inhibitors, glucagon-like peptide-1, a glucagon-like peptide-1analogue, a glucagon-like peptide-1 agonist, amylin, an amylin analogue,an amylin agonist, an aldose reductase inhibitor, an advanced glycationend products formation inhibitor, a protein kinase C inhibitor, aγ-aminobutyric acid antagonist, a sodium channel antagonist, atranscript factor NF-κB inhibitor, a lipid peroxidase inhibitor, anN-acetylated-α-linked-acid-dipeptidase inhibitor, insulin-like growthfactor-I, platelet-derived growth factor, a platelet derived growthfactor analogue, epidermal growth factor, nerve growth factor, acarnitine derivative, uridine, 5-hydroxy-1-methylhydantoin, EGB-761,bimoclomol, sulodexide, Y-128, an angiotensin-converting enzymeinhibitor, a neutral endo-peptidase inhibitor, an angiotensin IIreceptor antagonist, an endothelin-converting enzyme inhibitor, anendothelin receptor antagonist and a diuretic agent, and the diseaseassociated with hyperglycemia is diabetic complications;

[18] a pharmaceutical combination as described in the above [17] whereina component (B) is at least one member selected from the groupconsisting of an aldose reductase inhibitor, an angiotensin-convertingenzyme inhibitor, a neutral endopeptidase inhibitor and an angiotensinII receptor antagonist;

[19] a pharmaceutical combination as described in the above [13] whereina component (B) is at least one member selected from the groupconsisting of an insulin sensitivity enhancer, a glucose absorptioninhibitor, a biguanide, an insulin secretion enhancer, an insulinanalogue, a glucagon receptor antagonist, an insulin receptor kinasestimulant, a tripeptidyl peptidase II inhibitor, a dipeptidyl peptidaseIV inhibitor, a protein tyrosine phosphatase-1B inhibitor, a glycogenphosphorylase inhibitor, a glucose-6-phosphatase inhibitor, afructose-bisphosphatase inhibitor, a pyruvate dehydrogenase inhibitor, ahepatic gluconeogenesis inhibitor, D-chiroinsitol, a glycogen synthasekinase-3 inhibitor, glucagon-like peptide-1, a glucagon-like peptide-1analogue, a glucagon-like peptide-1 agonist, amylin, an amylin analogue,an amylin agonist, a β₃-adrenoceptor agonist and an appetitesuppressant, and the disease associated with hyperglycemia is obesity;

[20] a pharmaceutical combination as described in the above [19] whereina component (B) is at least one member selected from the groupconsisting of a β₃-adrenoceptor agonist and an appetite suppressant;

[21] a pharmaceutical combination as described in the above [20] whereinthe appetite suppressant is a drug selected from the group consisting ofa monoamine reuptake inhibitor, a serotonin reuptake inhibitor, aserotonin releasing stimulant, a serotonin agonist, a noradrenalinereuptake inhibitor, a noradrenaline releasing stimulant, anα₁-adrenoceptor agonist, a β₂-adrenoceptor agonist, a dopamine agonist,a cannabinoid receptor antagonist, a γ-aminobutyric acid receptorantagonist, a H₃-histamine antagonist, L-histidine, leptin, a leptinanalogue, a leptin receptor agonist, a melanocortin receptor agonist,α-melanocyte stimulating hormone, cocaine-and amphetamine-regulatedtranscript, mahogany protein, an enterostatin agonist, calcitonin,calcitonin-gene-related peptide, bombesin, a cholecystokinin agonist,corticotropin-releasing hormone, a corticotropin-releasing hormoneanalogue, a corticotropin-releasing hormone agonist, urocortin,somatostatin, a somatostatin analogue, a somatostatin receptor agonist,pituitary adenylate cyclase-activating peptide, brain-derivedneurotrophic factor, ciliary neurotrophic factor, thyrotropin-releasinghormone, neurotensin, sauvagine, a neuropeptide Y antagonist, an opioidpeptide antagonist, a galanin antagonist, a melanin-concentratinghormone receptor antagonist, an agouti-related protein inhibitor and anorexin receptor antagonist;

[22] a method for the prevention or treatment of a disease associatedwith hyperglycemia, which comprises administering an effective amount of(A) a nitrogen-containing heterocyclic derivative as described in theabove [1] or [2], or a pharmaceutically acceptable salt thereof, or aprodrug thereof, in combination with (B) at least one member selectedfrom the group consisting of an insulin sensitivity enhancer, a glucoseabsorption inhibitor, a biguanide, an insulin secretion enhancer,insulin or an insulin analogue, a glucagon receptor antagonist, aninsulin receptor kinase stimulant, a tripeptidyl peptidase II inhibitor,a dipeptidyl peptidase IV inhibitor, a protein tyrosine phosphatase-1Binhibitor, a glycogen phosphorylase inhibitor, a glucose-6-phosphataseinhibitor, a fructose-bisphosphatase inhibitor, a pyruvate dehydrogenaseinhibitor, a hepatic gluconeogenesis inhibitor, D-chiroinsitol, aglycogen synthase kinase-3 inhibitor, glucagon-like peptide-1, aglucagon-like peptide-1 analogue, a glucagon-like peptide-1 agonist,amylin, an amylin analogue, an amylin agonist, an aldose reductaseinhibitor, an advanced glycation end products formation inhibitor, aprotein kinase C inhibitor, a γ-aminobutyric acid receptor antagonist, asodium channel antagonist, a transcript factor NF-κB inhibitor, a lipidperoxidase inhibitor, an N-acetylated-α-linked-acid-dipeptidaseinhibitor, insulin-like growth factor-I, platelet-derived growth factor,a platelet-derived growth factor analogue, epidermal growth factor,nerve growth factor, a carnitine derivative, uridine,5-hydroxy-1-methylhydantoin, EGB-761, bimoclomol, sulodexide, Y-128, ahydroxymethyl-glutaryl coenzyme A reductase inhibitor, a fibric acidderivative, a β₃-adrenoceptor agonist, an acyl-coenzyme A: cholesterolacyltransferase inhibitor, probcol, a thyroid hormone receptor agonist,a cholesterol absorption inhibitor, a lipase inhibitor, a microsomaltriglyceride transfer protein inhibitor, a lipoxygenase inhibitor, acarnitine palmitoyl-transferase inhibitor, a squalene synthaseinhibitor, a low-density lipoprotein receptor enhancer, a nicotinic acidderivative, a bile acid sequestrant, a sodium/bile acid cotransporterinhibitor, a cholesterol ester transfer protein inhibitor, an appetitesuppressant, an angiotensin-converting enzyme inhibitor, a neutralendopeptidase inhibitor, an angiotensin II receptor antagonist, anendothelin-converting enzyme inhibitor, an endothelin receptorantagonist, a diuretic agent, a calcium antagonist, a vasodilatingantihypertensive agent, a sympathetic blocking agent, a centrally actingantihypertensive agent, an α₂-adrenoceptor agonist, an antiplateletsagent, a uric acid synthesis inhibitor, a uricosuric agent and a urinaryalkalinizer;

[23] a use of (A) a nitrogen-containing heterocyclic derivative asdescribed in the above [1] or [2], or a pharmaceutically acceptable saltthereof, or a prodrug thereof, and (B) at least one member selected fromthe group consisting of an insulin sensitivity enhancer, a glucoseabsorption inhibitor, a biguanide, an insulin secretion enhancer,insulin or an insulin analogue, a glucagon receptor antagonist, aninsulin receptor kinase stimulant, a tripeptidyl peptidase II inhibitor,a dipeptidyl peptidase IV inhibitor, a protein tyrosine phosphatase-1Binhibitor, a glycogen phosphorylase inhibitor, a glucose-6-phosphataseinhibitor, a fructose-bisphosphatase inhibitor, a pyruvate dehydrogenaseinhibitor, a hepatic gluconeogenesis inhibitor, D-chiroinsitol, aglycogen synthase kinase-3 inhibitor, glucagon-like peptide-1, aglucagon-like peptide-1 analogue, a glucagon-like peptide-1 agonist,amylin, an amylin analogue, an amylin agonist, an aldose reductaseinhibitor, an advanced glycation end products formation inhibitor, aprotein kinase C inhibitor, a γ-aminobutyric acid receptor antagonist, asodium channel antagonist, a transcript factor NF-κB inhibitor, a lipidperoxidase inhibitor, an N-acetylated-α-linked-acid-dipeptidaseinhibitor, insulin-like growth factor-I, platelet-derived growth factor,a platelet-derived growth factor analogue, epidermal growth factor,nerve growth factor, a carnitine derivative, uridine,5-hydroxy-1-methylhydantoin, EGB-761, bimoclomol, sulodexide, Y-128, ahydroxymethyl-glutaryl coenzyme A reductase inhibitor, a fibric acidderivative, a β₃-adrenoceptor agonist, an acyl-coenzyme A: cholesterolacyltransferase inhibitor, probcol, a thyroid hormone receptor agonist,a cholesterol absorption inhibitor, a lipase inhibitor, a microsomaltriglyceride transfer protein inhibitor, a lipoxygenase inhibitor, acarnitine palmitoyl-transferase inhibitor, a squalene synthaseinhibitor, a low-density lipoprotein receptor enhancer, a nicotinic acidderivative, a bile acid sequestrant, a sodium/bile acid cotransporterinhibitor, a cholesterol ester transfer protein inhibitor, an appetitesuppressant, an angiotensin-converting enzyme inhibitor, a neutralendopeptidase inhibitor, an angiotensin II receptor antagonist, anendothelin-converting enzyme inhibitor, an endothelin receptorantagonist, a diuretic agent, a calcium antagonist, a vasodilatingantihypertensive agent, a sympathetic blocking agent, a centrally actingantihypertensive agent, an α₂-adrenoceptor agonist, an antiplateletsagent, a uric acid synthesis inhibitor, a uricosuric agent and a urinaryalkalinizer, for the manufacture of a pharmaceutical composition for theprevention or treatment of a disease associated with hyperglycemia; andthe like.

In the present invention, the term “C₁₋₆ alkyl group” means astraight-chained or branched alkyl group having 1 to 6 carbon atoms suchas a methyl group, an ethyl group, a propyl group, an isopropyl group, abutyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, apentyl group, an isopentyl group, a neopentyl group, a tert-pentylgroup, a hexyl group or the like; the term “C₂₋₆ alkenyl group” means astraight-chained or branched alkenyl group having 2 to 6 carbon atomssuch as a vinyl group, an allyl group, a 1-propenyl group, anisopropenyl group, a 1-butenyl group, a 2-butenyl group, a 2-methylallylgroup or the like; and the term “C₂₋₆ alkynyl group” means astraight-chained or branched alkynyl group having 2 to 6 carbon atomssuch as an ethynyl group, a 2-propinyl group or the like. The term “C₂₋₇acyl group” means a straight-chained or branched acyl group having 2 to7 carbon atoms such as an acetyl group, a propionyl group, a butyrylgroup, an isobutyryl group, a valeryl group, a pivaloyl group, ahexanoyl group or the like; the term “C₃₋₈ cycloalkyl group” means acyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexylgroup, a cycloheptyl group or a cyclooctyl group; and the term “C₆₋₁₀aryl group” means a phenyl group or a naphthyl group. The term “C₂₋₉heterocycloalkyl group” means a group derived from a 3 to 8-memberedheterocycloalkyl group containing the same or different 1 or 2 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom inthe ring such as morpholine, thiomorpholine, tetrahydrofuran,tetrahydropyran, aziridine, azetidine, pyrrolidine, imidazolidine,oxazoline, piperidine, piperazine, pyrazolidine or the like, or a groupderived from a 5 or 6-membered heterocycloalkyl group as defined abovefused with an aliphatic or aromatic carbocycle or a heterocycle such asa cyclohexane ring, a benzene ring, a pyridine ring or the like. Theterm “C₁₋₉ heteroaryl group” means a group derived from a 5 or6-membered heteroaryl group containing the same or different 1 to 4hetero atoms selected from an oxygen atom, a sulfur atom and a nitrogenatom in the ring such as thiazole, oxazole, isothiazole, isoxazole,pyridine, pyrimidine, pyrazine, pyridazine, pyrrole, thiophene,imidazole, pyrazole, oxadiazole, thiadiazole, tetrazole, furazan or thelike, or a group derived from the above heteroaryl group fused with a 5or 6-membered aromatic carbocycle or heterocycle such as a benzene ring,a pyrazole ring, a pyridine ring or the like. The term “halogen atom”means a fluorine atom, a chlorine atom, a bromine atom or an iodineatom.

In the present invention, the term “prodrug” means a compound which isconverted into a nitrogen-containing heterocyclic derivative representedby the above general formula (I) as an active form thereof in vivo. Asprodrugs of a nitrogen-containing heterocyclic derivative represented bythe above general formula (I) or pharmaceutically acceptable salts, forexample, a compound represented by the general formula:

wherein P represents a group forming a prodrug; and X¹, X², X³, X⁴ and Rhave the same meanings as defined above, or a pharmaceuticallyacceptable salt thereof are illustrated.

As examples of groups forming prodrugs, a hydroxy-protective group whichcan be used generally in a prodrug such as a C₂₋₂₀ acyl group, a C₁₋₆alkyl-O—C₂₋₇ acyl group, a C₁₋₆ alkyl-OC(═O)—C₂₋₇ acyl group, C₁₋₆alkyl-OC(═O)—, C₁₋₆ alkyl-O—C₁₋₆alkyl-OC(═O)—, a benzoyl group, aC₂₋₇acyl-O-methyl group, a 1-(C₂₋₇acyl-O-) ethyl group, aC₁₋₆alkyl-OC(═O)O-methyl group, a 1-(C₁₋₆ alkyl-OC(═O)O-)ethyl group, aC₃₋₈ cycloalkyl-OC(═O)O-methyl group, a 1-(C₃₋₈cycloalkyl-OC(═O)O-)ethyl group, an ester group condensed with an aminoacid, a phosphoric acid derivative or a cinnamic acid derivative and thelike can be illustrated, and an amino-protective group which can be usedgenerally in a prodrug such as a C₂₋₇ acyl group, a C₁₋₆ alkyl-O—C₂₋₇acyl group, a C₁₋₆ alkyl-OC(═O)—C₂₋₇ acyl group, C₁₋₆ alkyl-OC(═O)—,C₁₋₆ alkyl-O—C₁₋₆alkyl-OC(═O)—, a benzoyl group, a C₂₋₇acyl-O-methylgroup, a 1-(C₂₋₇acyl-O-)ethyl group, a C₁₋₆alkyl-OC(═O)O-methyl group, a1-(C₁₋₆ alkyl-OC(═O)O-)ethyl group, a C₃₋₈ cycloalkyl-OC(═O)O-methylgroup, a 1-(C₃₋₈ cycloalkyl-OC(═O)O-)ethyl group, an amide groupcondensed with an amino acid and the like can be illustrated. Moreover,a sulfonamide-protective group which can be used generally in a prodrugsuch as a C₂₋₇ acyl-O-methyl group, a 1-(C₂₋₇ acyl-O-)ethyl group, aC₁₋₆alkyl-OC(═O)O-methyl group, a 1-(C₁₋₆ alkyl-OC(═O)O-)ethyl group, aC₃₋₈ cycloalkyl-OC(═O)O-methyl group, a 1-(C₃₋₈cycloalkyl-OC(═O)O-)ethyl group and the like can be illustrated.Furthermore, as examples of groups forming prodrugs, a sugar residuesuch as a glucopyranosyl group, a galactopyranosyl group and the likecan be illustrated, for example, such a group can be introduced into thehydroxy group at the 4 or 6-position of the glucopyranosyl group. Of thecompounds of the present invention, in a prodrug, a group forming aprodrug may be at any hydroxy group, amino group, sulfonamide group orthe like, and two or more such groups are acceptable. The term “C₂₋₂₀acyl group” means a straight-chained or branched acyl group having 2 to20 carbon atoms such as an acetyl group, a propionyl group, a butyrylgroup, an isobutyryl group, a valeryl group, a pivaloyl group, ahexanoyl group, a lauroyl group, a myristoyl group, a palmitoyl group, astearoyl group or the like.

The term “hydroxy-protective group” means a hydroxy-protective groupused in general organic syntheses such as a benzyl group, ap-methoxybenzyl group, a p-nitrobenzyl group, a methoxymethyl group, amethyl group, an acetyl group, a tert-butyldimethylsilyl group, an allylgroup, a benzoyl group, a pivaloyl group, a benzyloxycarbonyl group, a2-trimethylsilylethoxymethyl group or the like; the term“thiol-protective group” means a thiol-protective group used in generalorganic syntheses such as a benzyl group, a p-methoxybenzyl group, ap-nitrobenzyl group, an acetyl group, a benzoyl group, a pivaloyl group,a benzyloxycarbonyl group or the like; the term “amino-protective group”means an amino-protective group used in general organic syntheses suchas a benzyloxycarbonyl group, a tert-butoxycarbonyl group, a benzylgroup, a p-methoxybenzyl group, a trifluoroacetyl group, an acetyl groupor the like; and the term “carboxy-protective group” means acarboxy-protective group used in general organic syntheses such as abenzyl group, a tert-butyldimethylsilyl group, an allyl group or thelike.

As examples of nitrogen-containing heterocyclic derivatives representedby the above general formula (I) of the present invention, variouspyridine derivatives, various pyridazine derivatives, various pyrimidinederivatives, various pyrazine derivatives, various triazine derivativesand various tetrazine derivatives can be illustrated. In addition, incases that there are tautomers in the present compounds, the presentinvention includes all tautomers.

The nitrogen-containing heterocyclic derivatives represented by theabove general formula (I) of the present invention and prodrugs thereofcan be prepared, for example, according to the reactions described bythe following Scheme 1.

wherein L represents a hydroxy-protective group; P represents a groupforming a prodrug; Y¹ represents a leaving group such as a chlorineatom, a bromine atom or the like; and X¹, X², X³, X⁴ and R have the samemeanings as defined above.Process 1

A corresponding compound represented by the above general formula (II)can be prepared by subjecting an alcohol compound represented by theabove formula (III) or a salt thereof to glycosidation using a sugardonor such as acetobromo-α-D-glucose in the presence of a silver saltsuch as silver carbonate, silver oxide or the like or a base such aspotassium carbonate, sodium hydride or the like in an inert solvent. Asthe solvent used in the glycosidation reaction, for example,acetonitrile, tetrahydrofuran, dichloromethane, toluene,N,N-dimethyl-formamide, a mixed solvent and the like can be illustrated.The reaction temperature is usually from room temperature to refluxtemperature, and the reaction time is usually from 2 hours to 2 days,varying based on a used starting material, solvent and reactiontemperature.

Process 2

A nitrogen-containing heterocyclic derivative represented by the abovegeneral formula (I) of the present invention can be prepared bysubjecting a compound represented by the above general formula (II) toalkaline hydrolysis. As the solvent used in the alkaline hydrolysis,methanol, ethanol, tetrahydrofuran, water, a mixed solvent thereof andthe like can be illustrated, and as the base used, sodium hydroxide,potassium hydroxide, sodium methoxide, sodium ethoxide and the like canbe illustrated. The reaction temperature is usually from 0° C. to roomtemperature, and the reaction time is usually from 30 minutes to 6hours, varying based on a used starting material, solvent and reactiontemperature.

Process 3

A prodrug of a nitrogen-containing heterocyclic derivative representedby the above general formula (I) (for example, a prodrug represented bythe above general formula (Ia)) can be prepared by introducinghydroxy-protective groups generally capable for use in a prodrug intohydroxy groups of a nitrogen-containing heterocyclic derivativerepresented by the above general formula (I) using, for example, anagent for introducing a hydroxy-protective group represented by theabove general formula (IV) in the usual way.

For example, a compound represented by the above general formula (III)used as a starting material in the above production method (Scheme 1)can be prepared according to the reactions as described in the followingScheme 2.

wherein M¹ represents a hydroxy-protective group; M² represents ahydrogen atom or a hydroxy-protective group; and X¹, X², X³, X⁴ and Rhave the same meanings as defined above.Process 4

A compound represented by the above general formula (VI) can be preparedby subjecting a compound represented by the above general formula (V) tooxidation using a Dess-Martin reagent in an inert solvent. As thesolvent used in the oxidation, for example, dichloromethane, chloroform,a mixed solvent thereof or the like can be illustrated. The reactiontemperature is usually from 0° C. to reflux temperature, and thereaction time is usually from 10 minutes to 1 day, varying based on aused starting material, solvent and reaction temperature.

Process 5

A compound represented by the above general formula (III) can beprepared by subjecting a compound represented by the above generalformula (VI) to 1) hydrogenation in the presence or absence of an acidsuch as hydrochloric acid using a palladium catalyst such aspalladium-carbon powder or the like in an inert solvent under a hydrogenatmosphere, or to 2) reduction using a reducing agent. As the solventused in the 1) hydrogenation, for example, methanol, ethanol,tetrahydrofuran, ethyl acetate, acetic acid, isopropanol, a mixedsolvent thereof or the like can be illustrated. The reaction temperatureis usually from 0° C. to reflux temperature, and the reaction time isusually from 30 minutes to 1 day, varying based on a used startingmaterial, solvent and reaction temperature. The 2) reduction using areducing agent can be performed in the presence of a Lewis acid such astrifluoroborate or the like using a reducing agent such as sodiumcyanoborohydride or the like in an inert solvent such astetrahydrofuran. The reaction temperature is usually from roomtemperature to reflux temperature, and the reaction time is usually from1 hour to 1 day, varying based on a used starting material, solvent andreaction temperature.

A compound represented by the above general formula (III) used as astarting material in the above production method (Scheme 1) can be alsoprepared, for example, according to the reactions as described in thefollowing Scheme 3.

wherein M¹, X¹, X², X³, X⁴ and R have the same meanings as definedabove.Process 6

A compound represented by the above general formula (III) can beprepared by subjecting a compound represented by the above generalformula (V) to hydrogenation in the presence or absence of an acid suchas hydrochloric acid using a palladium catalyst such as palladium-carbonpowder in an inert solvent under a hydrogen atmosphere. As the solventused in the hydrogenation, for example, methanol, ethanol,tetrahydrofuran, ethyl acetate, acetic acid, isopropanol, a mixedsolvent thereof or the like can be illustrated. The reaction temperatureis usually from 0° C. to reflux temperature, and the reaction time isusually from 30 minutes to 1 day, varying based on a used startingmaterial, solvent and reaction temperature.

Process 7

A compound represented by the above general formula (VII) can beprepared by removing the protective group M¹ of a compound representedby the above general formula (V) in the usual way.

Process 8

A compound represented by the above general formula (III) can beprepared by subjecting a compound represented by the above generalformula (VII) to hydrogenation in the presence or absence of an acidsuch as hydrochloric acid using a palladium catalyst such aspalladium-carbon powder in an inert solvent under a hydrogen atmosphere.As the solvent used in the hydrogenation, for example, methanol,ethanol, tetrahydrofuran, ethyl acetate, acetic acid, isopropanol, amixed solvent thereof or the like can be illustrated. The reactiontemperature is usually from 0° C. to reflux temperature, and thereaction time is usually from 30 minutes to 1 day, varying based on aused starting material, solvent and reaction temperature.

Of compounds represented by the above general formula (III) used asstarting materials in the above production method (Scheme 1), a compoundrepresented by the following general formula (IIIa) can be prepared, forexample, according to the reactions as described in the following Scheme4.

wherein Y² represents a chlorine atom or a bromine atom; and R² and Rhave the same meanings as defined above.Process 9

A compound represented by the above general formula (X) can be obtainedby dissolving a compound represented by the above general formula (VIII)in an inert solvent, allowing the compound to react with lithium2,2,6,6-tetramethylpiperidide usually at −100° C. to −50° C. and usuallyfor 10 minutes to 2 hours, and allowing the resulting compound to reactwith a compound represented by the above general formula (IX) usually at−100° C. to room temperature. As the inert solvent used,tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, a mixed solventthereof or the like can be illustrated. The reaction time of thecondensation reaction is usually from 30 minutes to 6 hours, varyingbased on a used starting material, solvent and reaction temperature.

Process 10

A compound represented by the above general formula (XI) can be preparedby allowing a compound represented by the above general formula (X) toreact with benzyl alcohol in the presence oftris[2-(2-methoxyethoxy)ethyl]amine using a base such as potassiumhydroxide, sodium hydroxide, potassium carbonate, sodium carbonate,sodium hydrogen carbonate or the like, in a solvent such as toluene,benzene or the like. The reaction temperature is usually from roomtemperature to reflux temperature, and the reaction time is usually from1 hour to 1 day, varying based on a used starting material, solvent andreaction temperature

Process 11

A compound represented by the above general formula (IIIa) can beprepared by subjecting a compound represented by the above generalformula (XI) to hydrogenation in the presence or absence of an acid suchas hydrochloric acid using a palladium catalyst such as palladium-carbonpowder in an inert solvent under a hydrogen atmosphere. As the solventused in the hydrogenation, for example, methanol, ethanol,tetrahydrofuran, ethyl acetate, acetic acid, isopropanol, a mixedsolvent thereof or the like can be illustrated. The reaction temperatureis usually from room temperature to reflux temperature, and the reactiontime is usually from 1 hour to 1 day, varying based on a used startingmaterial, solvent and reaction temperature.

Of compounds represented by the above general formula (III) used asstarting materials in the above production method (Scheme 1), a compoundrepresented by the following general formula (IIIb) can be alsoprepared, for example, according to the reactions as described in thefollowing Scheme 5.

wherein R⁵represents a lower alkyl group; Y³ represents a leaving groupsuch as a halogen atom, a mesyloxy group, a tosyloxy group or the like;and R², R⁴ and R have the same meanings as defined above.Process 12

A compound represented by the above general formula (XIV) can beprepared by subjecting a compound represented by the above generalformula (XII) to 1) condensation with a benzyl derivative represented bythe above general formula (XIII) in the presence of a base such assodium hydride, potassium tert-butoxide or the like in a solvent such as1,2-dimethoxyethane, tetrahydrofuran, N,N-dimethylformamide,N,N-dimethyl-acetamide or the like, or to 2) condensation with a benzylderivative represented by the above general formula (XIII) in thepresence or absence of lithium bromide or lithium chloride using a basesuch as diisopropylethylamine, triethylamine,1,8-diazabicyclo-[5,4,0]-7-undecene or the like in a solvent such astetrahydrofuran, diethyl ether, N,N-dimethylformamide,N,N-dimethylacetamide or the like. At the reaction 1), the reactiontemperature is usually from room temperature to reflux temperature, andthe reaction time is usually from 1 hour to 1 day, varying based on aused starting material, solvent and reaction temperature. In addition,at the reaction 2), the reaction temperature is usually from roomtemperature to reflux temperature, and the reaction time is usually from1 hour to 1 day, varying based on a used starting material, solvent andreaction temperature.

Process 13

A compound represented by the above general formula (IIIb) can beobtained by allowing a compound represented by the above general formula(XIV) to react with a compound represented by the above general formula(XV) or a salt thereof in the presence or absence of a base such assodium methoxide, sodium ethoxide or the like in an alcoholic solvent.As the alcoholic solvent used in the reaction, for example, methanol,ethanol, propanol, a mixed solvent thereof or the like can beillustrated. The reaction temperature is usually from room temperatureto reflux temperature, and the reaction time is usually from 2 hours to2 days, varying based on a used starting material, solvent and reactiontemperature.

Of compounds represented by the above general formula (III) used asstarting materials in the above production method (Scheme 1), a compoundrepresented by the following general formula (IIIc) can be alsoprepared, for example, according to the reactions as described in thefollowing Scheme 6.

wherein R⁴, R⁵ and R have the same meanings as defined above.Process 14

A compound represented by the above general formula (XVII) can beobtained by reducing a compound represented by the above general formula(XVI) using a reducing agent such as borane-tetrahydrofuran complex,borane-dimethylsulfide complex or the like in an inert solvent. As theinert solvent used in the reduction, tetrahydrofuran, diethyl ether, amixed solvent thereof or the like can be illustrated. The reactiontemperature is usually from 0° C. to reflux temperature, and thereaction time is usually from 1 hour to 1 day, varying based on a usedstarting material, solvent and reaction temperature. In addition, astarting material represented by the above general formula (XVI) can becommercially available or prepared by reaction according to a manner asdescribed in literature or an analogous method thereof, for example, J.Org. Chem., Vol. 37, pp. 555-559 (1972), SYNLETT, pp. 137-138 (1993)

Process 15

A compound represented by the above general formula (XVIII) can beprepared by subjecting a compound represented by the above generalformula (XVII) to oxidation using a Dess-Martin reagent in an inertsolvent. As the solvent used in the oxidation, for example,dichloromethane, chloroform, a mixed solvent thereof or the like can beillustrated. The reaction temperature is usually from 0° C. to refluxtemperature, and the reaction time is usually from 30 minutes to 1 day,varying based on a used starting material, solvent and reactiontemperature.

Process 16

A compound represented by the above general formula (IIIc) can beobtained by subjecting a compound represented by the above generalformula (XVIII) to cyclization by reaction with hydrazine or a hydratethereof or a salt thereof in a solvent such as methanol, ethanol,toluene, benzene or a mixed solvent thereof, and then to oxidation usingselenium dioxide or the like in an alcoholic solvent such as methanol,ethanol or the like. At the cyclization reaction, the reactiontemperature is usually from room temperature to reflux temperature, andthe reaction time is usually from 30 minutes to 1 day, varying based ona used starting material, solvent and reaction temperature. At theoxidation reaction, the reaction temperature is usually from roomtemperature to reflux temperature, and the reaction time is usually from30 minutes to 2 days, varying based on a used starting material, solventand reaction temperature.

A compound represented by the above general formula (V) used as astarting material in the above production method (Scheme 2) can beprepared, for example, according to the reactions as described in thefollowing Scheme 7.

wherein X¹, X², X³, X⁴, R and M¹ have the same meanings as definedabove.Process 17

A compound represented by the above general formula (XXI) can beobtained by introducing a protective group M¹ into the hydroxy group ofa compound represented by the above general formula (XX) in the usualway.

Process 18

A compound represented by the above general formula (V) can be preparedby dissolving a compound represented by the above general formula (XXI)in an inert solvent, allowing the compound to react with an organolithium such as tert-butyllithium, n-butyllithium or the like usually at−100° C. to 0° C. usually for 10 minutes to 2 hours, and then allowingthe resulting compound to react with a compound represented by the abovegeneral formula (IX) added to the reaction mixture, at −100° C. to roomtemperature. As the inert solvent used in the present reaction,tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, a mixed solventthereof or the like can be illustrated. The reaction time at thecondensation reaction is usually from 30 minutes to 6 hours, varyingbased on a used starting material, solvent and reaction temperature.

A compound represented by the above general formula (V) used as astarting material in the above production method (Scheme 2) can be alsoprepared, for example, according to the reaction as described in thefollowing Scheme 8.

wherein Z represents MgBr, MgCl, MgI or a lithium atom; X¹, X², X³, X⁴,R and M¹ have the same meanings as defined above.Process 19

A compound represented by the above general formula (V) can be obtainedby subjecting a compound represented by the above general formula (XXI)to condensation with a compound represented by the above general formula(XXII) in an inert solvent. As the solvent used in the condensationreaction, for example, tetrahydrofuran, diethyl ether,1,2-dimethoxyethane, a mixed solvent thereof or the like can beillustrated. The reaction temperature is usually from −100° C. to roomtemperature, and the reaction time is usually from 30 minutes to 6hours, varying based on a used starting material, solvent and reactiontemperature.

A compound represented by the above general formula (XXI) used as astarting material in the above production method (Scheme 8) can beprepared, for example, according to the reactions as described in thefollowing Scheme 9.

wherein X¹, X², X³, X⁴, R⁵ and M¹ have the same meanings as definedabove.Process 20

A compound represented by the above general formula (XXI) can beobtained by dissolving a compound represented by the above generalformula (XX) in an inert solvent, allowing the compound to react with anorgano lithium such as tert-butyllithium, n-butyllithium or the likeusually at −100° C. to 0° C. usually for 10 minutes to 2 hours, thenadding N,N-dimethylformamide, allowing the mixture to react usually at−100° C. to room temperature usually for 30 minutes to 1 day, andtreating the reaction mixture with an aqueous acidic solution. As theinert solvent used, for example, tetrahydrofuran, diethyl ether,1,2-dimethoxyethane, a mixed solvent thereof or the like can beillustrated, and as an aqueous acidic solution, for example, an aqueoussolution of acetic acid, hydrochloric acid, succinic acid, oxalic acidor the like can be illustrated. The treatment time in the aqueous acidicsolution is usually from 5 minutes to 30 minutes, varying based on aused aqueous acidic solution and reaction temperature.

Process 21

A compound represented by the above general formula (XXIII) can beprepared by introducing a protective group M¹ into the hydroxy group ofa compound represented by the above general formula (XXII) in the usualway.

Process 22

A compound represented by the above general formula (XXI) can beobtained by subjecting a compound represented by the above generalformula (XXIII) using a reducing agent such as diisobutylaluminumhydride or the like in an inert solvent. As the solvent used in thereaction, for example, tetrahydrofuran, dichloromethane, a mixed solventthereof or the like can be illustrated. The reaction temperature isusually from −100° C. to room temperature, and the reaction time isusually from 1 hour to 6 days, varying based on a used startingmaterial, solvent and reaction temperature.

Process 23

A compound represented by the above general formula (XXV) can beprepared by introducing a protective group M¹ into the hydroxy group ofa compound represented by the above general formula (XXIV) in the usualway.

Process 24

A compound represented by the above general formula (XXI) can beobtained by subjecting a compound represented by the above generalformula (XXV) to 1) reduction using a reducing agent such asdiisobutylaluminum hydride in an inert solvent, and then to 2) oxidationusing an oxidizing agent such as a Dess-Martin reagent in an inertsolvent. As the solvent used in the reduction, for example,tetrahydrofuran, dichloromethane, a mixed solvent thereof or the likecan be illustrated, the reaction temperature is usually from −20° C. toreflux temperature, and the reaction time is usually from 1 hour to 1day, varying based on a used starting material, solvent and reactiontemperature. As the solvent used in the oxidation, for example,chloroform, dichloromethane or the like can be illustrated, the reactiontemperature is usually from 0° C. to reflux temperature, and thereaction time is usually from 1 hour to 1 day, varying based on a usedstarting material, solvent and reaction temperature.

In the above production methods, a compound having a hydroxy group, athiol group, an amino group and/or a carboxylic group can be subjectedto the reaction after optionally introducing a protective group in theusual way as occasion demands. The protective group can be removed inthe usual way in any subsequent process as occasion demands.

The compounds represented by the above general formula (I) of thepresent invention obtained by the above production processes can beisolated and purified by conventional separation means such asfractional recrystallization, purification using chromatography, solventextraction and solid phase extraction.

The nitrogen-containing heterocyclic derivatives represented by theabove general formula (I) of the present invention and prodrugs thereofcan be converted into their pharmaceutically acceptable salts in theusual way. Examples of such salts include acid addition salts withmineral acids such as hydrochloric acid, hydrobromic acid, hydroiodicacid, sulfuric acid, nitric acid, phosphoric acid and the like, acidaddition salts with organic acids such as formic acid, acetic acid,methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid,propionic acid, citric acid, succinic acid, tartaric acid, fumaric acid,butyric acid, oxalic acid, malonic acid, maleic acid, lactic acid, malicacid, carbonic acid, glutamic acid, aspartic acid and the like, saltswith inorganic bases such as a sodium salt, a potassium salt and thelike, and addition salts with organic bases such as N-methyl-D-glucamin,N,N′-dibenzylethylenediamine, 2-aminoethanol,tris(hydroxymethyl)aminomethane, arginine, lysine and the like.

The compounds represented by the above general formula (I) of thepresent invention and salts thereof and prodrugs thereof include theirsolvates with pharmaceutically acceptable solvents such as ethanol andwater.

Among the nitrogen-containing heterocyclic derivatives represented bythe above general formula (I) of the present invention and prodrugsthereof, there are two optical isomers, R-isomer and S-isomer, in eachcompound having an asymmetric carbon atom excluding theglucopyranosyloxy moiety. In the present invention, either of R-isomeror S-isomer can be employed, and a mixture of both isomers can be alsoemployed.

The nitrogen-containing heterocyclic derivatives represented by theabove general formula (I) of the present invention and prodrugs thereofare able to show an activity of lowering blood glucose level by anexcellent inhibitory activity in human SGLT2. Therefore, they areextremely useful as drugs for the prevention or treatment of a diseaseassociated with hyperglycemia such as diabetes, diabetic complications(e.g., retinopathy, neuropathy, nephropathy, ulcer, macroangiopathy),obesity, hyperinsulinemia, glucose metabolism disorders, hyperlipidemia,hypercholesterolemia, hypertriglyceridemia, lipid metabolism disorders,a therosclerosis, hypertension, congestive heart failure, edema,hyperuricemia, gout or the like.

Furthermore, the compounds of the present invention can be suitably usedin combination with at least one member selected from drugs other thanSGLT2 inhibitors. Examples of the drugs which can be used in combinationwith the compounds of the present invention include an insulinsensitivity enhancer, a glucose absorption inhibitor, a biguanide, aninsulin secretion enhancer, an insulin preparation, a glucagon receptorantagonist, an insulin receptor kinase stimulant, a tripeptidylpeptidase II inhibitor, a dipeptidyl peptidase IV inhibitor, a proteintyrosine phosphatase-1B inhibitor, a glycogen phosphorylase inhibitor, aglucose-6-phosphatase inhibitor, a fructose-bisphosphatase inhibitor, apyruvate dehydrogenase inhibitor, a hepatic gluconeogenesis inhibitor,D-chiroinositol, a glycogen synthase kinase-3 inhibitor, glucagon-likepeptide-1, a glucagon-like peptide-1 analogue, a glucagon-like peptide-1agonist, amylin, an amylin analogue, an amylin agonist, an aldosereductase inhibitor, an advanced glycation end products formationinhibitor, a protein kinase C inhibitor, a γ-aminobutyric acid receptorantagonist, a sodium channel antagonist, a transcript factor NF-κBinhibitor, a lipid peroxidase inhibitor, anN-acetylated-α-linked-acid-dipeptidase inhibitor, insulin-like growthfactor-I, platelet-derived growth factor (PDGF), a platelet-derivedgrowth factor (PDGF) analogue (e.g., PDGF-AA, PDGF-BB, PDGF-AB),epidermal growth factor (EGF), nerve growth factor, a carnitinederivative, uridine, 5-hydroxy-1-methylhydantoin, EGB-761, bimoclomol,sulodexide, Y-128, a hydroxymethyl-glutaryl coenzyme A reductaseinhibitor, a fibric acid derivative, a β₃-adrenoceptor agonist, anacyl-coenzyme A: cholesterol acyltransferase inhibitor, probcol, athyroid hormone receptor agonist, a cholesterol absorption inhibitor, alipase inhibitor, a microsomal triglyceride transfer protein inhibitor,a lipoxygenase inhibitor, a carnitine palmitoyl transferase inhibitor, asqualene synthase inhibitor, a low-density lipoprotein receptorenhancer, a nicotinic acid derivative, a bile acid sequestrant, asodium/bile acid cotransporter inhibitor, a cholesterol ester transferprotein inhibitor, an appetite suppressant, an angiotensin-convertingenzyme inhibitor, a neutral endopeptidase inhibitor, an angiotensin IIreceptor antagonist, an endothelin-converting enzyme inhibitor, anendothelin receptor antagonist, a diuretic agent, a calcium antagonist,a vasodilating antihypertensive agent, a sympathetic blocking agent, acentrally acting antihypertensive agent, an α₂-adrenoceptor agonist, anantiplatelets agent, a uric acid synthesis inhibitor, a uricosuric agentand a urinary alkalinizer.

In case of uses of the compound of the present invention in combinationwith the above one or more drugs, the present invention includes eitherdosage forms of simultaneous administration as a single preparation orseparated preparations in way of same or different administration route,and administration at different dosage intervals as separatedpreparations in way of same or different administration route. Apharmaceutical combination comprising the compound of the presentinvention and the above one or more drugs includes both dosage forms asa single preparation and separated preparations for combination asmentioned above.

The compounds of the present invention can obtain more advantageouseffects than additive effects in the prevention or treatment of theabove diseases when using suitably in combination with the above drugs.Also, the administration dose can be decreased in comparison withadministration of either drug alone, or adverse effects ofcoadministrated drugs other than SGLT2 inhibitors can be avoided ordeclined.

Concrete compounds as the above drugs used for combination andpreferable diseases to be treated are exemplified as follows. However,the present invention is not limited thereto, and for example, theconcrete compounds include their free compounds, and their or otherpharmaceutically acceptable salts.

As insulin sensitivity enhancers, peroxisome proliferator-activatedreceptor-γ agonists such as troglitazone, pioglitazone hydrochloride,rosiglitazone maleate, sodium darglitazone, GI-262570, isaglitazone,LG-100641, NC-2100, T-174, DRF-2189, CLX-0921, CS-011, GW-1929,ciglitazone, sodium englitazone and NIP-221, peroxisomeproliferator-activated receptor-α agonists such as GW-9578 andBM-170744, peroxisome proliferator-activated receptor-α/γ agonists suchas GW-409544, KRP-297, NN-622, CLX-0940, LR-90, SB-219994, DRF-4158 andDRF-MDX8, retinoid X receptor agonists such as ALRT-268, AGN-4204,MX-6054, AGN-194204, LG-100754and bexarotene, and other insulinsensitivity enhancers such as reglixane, ONO-5816, MBX-102, CRE-1625,FK-614, CLX-0901, CRE-1633, NN-2344, BM-13125, BM-501050, HQL-975,CLX-0900, MBX-668, MBX-675, S-15261, GW-544, AZ-242, LY-510929,AR-H049020 and GW-501516 are illustrated. Insulin sensitivity enhancersare used preferably for diabetes, diabetic complications, obesity,hyperinsulinemia, glucose metabolism disorders, hyperlipidemia,hypercholesterolemia, hypertriglyceridemia, lipid metabolism disordersor atherosclerosis, and more preferably for diabetes, hyperinsulinemiaor glucose metabolism disorders because of improving the disturbance ofinsulin signal transduction in peripheral tissues and enhancing glucoseuptake into the tissues from the blood, leading to lowering bloodglucose level.

As glucose absorption inhibitors, α-glucosidase inhibitors such asacarbose, voglibose, miglitol, CKD-711, emiglitate, MDL-25,637,camiglibose and MDL-73,945, and α-amylase inhibitors such as AZM-127 areillustrated. Glucose absorption inhibitors are used preferably fordiabetes, diabetic complications, obesity, hyperinsulinemia or glucosemetabolism disorders, and more preferably for diabetes or glucosemetabolism disorders because of inhibiting the gastrointestinalenzymatic digestion of carbohydrates contained in foods, and inhibitingor delaying the absorption of glucose into the body.

As biguanides, phenformin, buformin hydrochloride, metforminhydrochloride and the like are illustrated. Biguanides are usedpreferably for diabetes, diabetic complications, hyperinsulinemia orglucose metabolism disorders, and more preferably for diabetes,hyperinsulinemia or glucose metabolism disorders because of loweringblood glucose level by inhibitory effects on hepatic gluconeogenesis,accelerating effects on anaerobic glycolysis in tissues or improvingeffects on insulin resistance in peripheral tissues.

As insulin secretion enhancers, tolbutamide, chlorpropamide, tolazamide,acetohexamide, glyclopyramide, glyburide (glibenclamide), gliclazide,1-butyl-3-metanilyl-urea, carbutamide, glibornuride, glipizide,gliquidone, glisoxapide, glybuthiazol, glybuzole, glyhexamide, sodiumglymidine, glypinamide, phenbutamide, tolcyclamide, glimepiride,nateglinide, mitiglinide calcium hydrate, repaglinide and the like areillustrated. Insulin secretion enhancers are used preferably fordiabetes, diabetic complications or glucose metabolism disorders, andmore preferably for diabetes or glucose metabolism disorders because oflowering blood glucose level by acting on pancreatic β-cells andenhancing the insulin secretion.

As insulin or insulin analogues, human insulin, animal-deprived insulinand human insulin analogues are illustrated. These agents are usedpreferably for diabetes, diabetic complications or glucose metabolismdisorders, and more preferably for diabetes or glucose metabolismdisorders.

As glucagon receptor antagonists, BAY-27-9955, NNC-92-1687 and the likeare illustrated; as insulin receptor kinase stimulants, TER-17411,L-783281, KRX-613 and the like are illustrated; as tripeptidyl peptidaseII inhibitors, UCL-1397 and the like are illustrated; as dipeptidylpeptidase IV inhibitors, NVP-DPP728A, TSL-225, P-32/98 and the like areillustrated; as protein tyrosine phosphatase 1B inhibitors, PTP-112,OC-86839, PNU-177496 and the like are illustrated; as glycogenphosphorylase inhibitors, NN-4201, CP-368296 and the like areillustrated; as fructose-bisphosphatase inhibitors, R-132917 and thelike are illustrated; as pyruvate dehydrogenase inhibitors, AZD-7545 andthe like are illustrated; as hepatic gluconeogenesis inhibitors,FR-225659 and the like are illustrated; as glucagon-like peptide-1analogues, exendin-4, CJC-1131 and the like are illustrated; asglucagon-like peptide 1 agonists; AZM-134, LY-315902 and the like areillustrated; and as amylin, amylin analogues or amylin agonists,pramlintide acetate and the like are illustrated. These drugs,glucose-6-phosphatase inhibitors, D-chiroinositol, glycogen synthasekinase-3 inhibitors, glucagon-like peptide-1 are used preferably fordiabetes, diabetic complications, hyperinsulinemia or glucose metabolismdisorders, and more preferably for diabetes or glucose metabolismdisorders.

As aldose reductase inhibitors, ascorbyl gamolenate, tolrestat,epalrestat, ADN-138, BAL-ARI8, ZD-5522, ADN-311, GP-1447, IDD-598,fidarestat, sorbinil, ponalrestat, risarestat, zenarestat, minalrestat,methosorbinil, AL-1567, imirestat, M-16209, TAT, AD-5467, zopolrestat,AS-3201, NZ-314, SG-210, JTT-811, lindolrestat and the like areillustrated. Aldose reductase inhibitors are preferably used fordiabetic complications because of inhibiting aldose reductase andlowering excessive intracellular accumulation of sorbitol in acceleratedpolyol pathway which are in continuous hyperglycemic condition in thetissues in diabetic complications.

As advanced glycation end products formation inhibitors, pyridoxamine,OPB-9195, ALT-946, ALT-711, pimagedine hydrochloride and the like areillustrated. Advanced glycation end products formation inhibitors arepreferably used for diabetic complications because of inhibitingformation of advanced glycation end products which are accelerated incontinuous hyperglycemic condition in diabetes and declining cellulardamage.

As protein kinase C inhibitors, LY-333531, midostaurin and the like areillustrated. Protein kinase C inhibitors are preferably used fordiabetic complications because of inhibiting protein kinase C activitywhich is accelerated in continuous hyperglycemic condition in diabetes.

As γ-aminobutyric acid receptor antagonists, topiramate and the like areillustrated; as sodium channel antagonists, mexiletine hydrochloride,oxcarbazepine and the like are illustrated; as transcrit factor NF-κBinhibitors, dexlipotam and the like are illustrated; as lipid peroxidaseinhibitors, tirilazad mesylate and the like are illustrated; asN-acetylated-α-linked-acid-dipeptidase inhibitors, GPI-5693 and the likeare illustrated; and as carnitine derivatives, carnitine, levacecarninehydrochloride, levocarnitine chloride, levocarnitine, ST-261 and thelike are illustrated. These drugs, insulin-like growth factor-I,platelet-derived growth factor, platelet derived growth factoranalogues, epidermal growth factor, nerve growth factor, uridine,5-hydroxy-1-methyl-hidantoin, EGB-761, bimoclomol, sulodexide and Y-128are preferably used for diabetic complications.

As hydroxymethyl glutaryl coenzyme A reductase inhibitors, sodiumcerivastatin, sodium pravastatin, lovastatin, simvastatin, sodiumfluvastatin, atorvastatin calcium hydrate, SC-45355, SQ-33600, CP-83101,BB-476, L-669262, S-2468, DMP-565, U-20685, BAY-x-2678, BAY-10-2987,calcium pitavastatin, calcium rosuvastatin, colestolone, dalvastatin,acitemate, mevastatin, crilvastatin, BMS-180431, BMY-21950,glenvastatin, carvastatin, BMY-22089, bervastatin and the like areillustrated. Hydroxymethyl glutaryl coenzyme A reductase inhibitors areused preferably for hyperlipidemia, hypercholesterolemia,hypertriglyceridemia, lipid metabolism disorders or atherosclerosis, andmore preferably for hyperlipidemia, hypercholesterolemia oratherosclerosis because of lowering blood cholesterol level byinhibiting hydroxymethyl glutaryl coenzyme A reductase.

As fibric acid derivatives, bezafibrate, beclobrate, binifibrate,ciprofibrate, clinofibrate, clofibrate, aluminum clofibrate, clofibricacid, etofibrate, fenofibrate, gemfibrozil, nicofibrate, pirifibrate,ronifibrate, simfibrate, theofibrate, AHL-157 and the like areillustrated. Fibric acid derivatives are used preferably forhyperinsulinemia, hyperlipidemia, hypercholesterolemia,hypertriglyceridemia, lipid metabolism disorders or atherosclerosis, andmore preferably for hyperlipidemia, hypertriglyceridemia oratherosclerosis because of activating hepatic lipoprotein lipase andenhancing fatty acid oxidation, leading to lowering blood triglyceridelevel.

As β₃-adrenoceptor agonists, BRL-28410, SR-58611A, ICI-198157, ZD-2079,BMS-194449, BRL-37344, CP-331679, CP-114271, L-750355, BMS-187413,SR-59062A, BMS-210285, LY-377604, SWR-0342SA, AZ-40140, SB-226552,D-7114, BRL-35135, FR-149175, BRL-26830A, CL-316243, AJ-9677, GW-427353,N-5984, GW-2696, YM178 and the like are illustrated. β₃-Adrenoceptoragonists are used preferably for obesity, hyperinsulinemia,hyperlipidemia, hypercholesterolemia, hypertriglyceridemia or lipidmetabolism disorders, and more preferably for obesity orhyperinsulinemia because of stimulating β₃-adrenoceptor in adiposetissue and enhancing the fatty acid oxidation, leading to induction ofenergy expenditure.

As acyl-coenzyme A: cholesterol acyltransferase inhibitors, NTE-122,MCC-147, PD-132301-2, DUP-129, U-73482, U-76807, RP-70676, P-06139,CP-113818, RP-73163, FR-129169, FY-038, EAB-309, KY-455, LS-3115,FR-145237, T-2591, J-104127, R-755, FCE-28654, YIC-C8-434, avasimibe,CI-976, RP-64477, F-1394, eldacimibe, CS-505, CL-283546, YM-17E,lecimibide, 447C88, YM-750, E-5324, KW-3033, HL-004, eflucimibe and thelike are illustrated. Acyl-coenzyme A: cholesterol acyltransferaseinhibitors are used preferably for hyperlipidemia,hyper-cholesterolemia, hypertriglyceridemia or lipid metabolismdisorders, and more preferably for hyperlipidemia orhyper-cholesterolemia because of lowering blood cholesterol level byinhibiting acyl-coenzyme A: cholesterol acyltransferase.

As thyroid hormone receptor agonists, sodium liothyronine, sodiumlevothyroxine, KB-2611 and the like are illustrated; as cholesterolabsorption inhibitors, ezetimibe, SCH-48461 and the like areillustrated; as lipase inhibitors, orlistat, ATL-962, AZM-131,RED-103004 and the like are illustrated; as carnitinepalmitoyltransferase inhibitors, etomoxir and the like are illustrated;as squalene synthase inhibitors, SDZ-268-198, BMS-188494, A-87049,RPR-101821, ZD-9720, RPR-107393, ER-27856 and the like are illustrated;as nicotinic acid derivatives, nicotinic acid, nicotinamide, nicomol,niceritrol, acipimox, nicorandil and the like are illustrated; as bileacid sequestrants, colestyramine, colestilan, colesevelam hydrochloride,GT-102-279 and the like are illustrated; as sodium/bile acidcotransporter inhibitors, 264W94, S-8921, SD-5613 and the like areillustrated; and as cholesterol ester transfer protein inhibitors,PNU-107368E, SC-795, JTT-705, CP-529414 and the like are illustrated.These drugs, probcol, microsomal triglyceride transfer proteininhibitors, lipoxygenase inhibitors and low-density lipoprotein receptorenhancers are preferably used for hyperlipidemia, hypercholesterolemia,hypertriglyceridemia or lipid metabolism disorders.

As appetite suppressants, monoamine reuptake inhibitors, serotoninreuptake inhibitors, serotonin releasing stimulants, serotonin agonists(especially 5HT_(2C)-agonists), noradrenalin reuptake inhibitors,noradrenalin releasing stimulants, α₁-adrenoceptor agonists,β₂-adrenoceptor agonists, dopamine agonists, cannabinoid receptorantagonists, γ-aminobutyric acid receptor antagonists, H₃-histamineantagonists, L-histidine, leptin, leptin analogues, leptin receptoragonists, melanocortin receptor agonists (especially, MC3-R agonists,MC4-R agonists), α-melanocyte stimulating hormone, cocaine-andamphetamine-regulated transcript, mahogany protein, enterostatinagonists, calcitonin, calcitonin-gene-related peptide, bombesin,cholecystokinin agonists (especially CCK-A agonists),corticotropin-releasing hormone, corticotropin-releasing hormoneanalogues, corticotropin-releasing hormone agonists, urocortin,somatostatin, somatostatin analogues, somatostatin receptor agonists,pituitary adenylate cyclase-activating peptide, brain-derivedneurotrophic factor, ciliary neurotrophic factor, thyrotropin-releasinghormone, neurotensin, sauvagine, neuropeptide Y antagonists, opioidpeptide antagonists, galanin antagonists, melanin-concentrating hormonereceptor antagonists, agouti-related protein inhibitors and orexinreceptor antagonists are illustrated. Concretely, as monoamine reuptakeinhibitors, mazindol and the like are illustrated; as serotonin reuptakeinhibitors, dexfenfluramine hydrochloride, fenfluramine, sibutraminehydrochloride, fluvoxamine maleate, sertraline hydrochloride and thelike are illustrated; as serotonin agonists, inotriptan,(+)-norfenfluramine and the like are illustrated; as noradrenalinereuptake inhibitors, bupropion, GW-320659 and the like are illustrated;as noradrenaline releasing stimulants, rolipram, YM-992 and the like areillustrated; as β₂-adrenoceptor agonists, amphetamine,dextroamphetamine, phentermine, benzphetamine, methamphetamine,phendimetrazine, phenmetrazine, diethylpropion, phenylpropanolamine,clobenzorex and the like are illustrated; as dopamine agonists, ER-230,doprexin, bromocriptine mesylate and the like are illustrated; ascannabinoid receptor antagonists, rimonabant and the like areillustrated; as γ-aminobutyric acid receptor antagonists, topiramate andthe like are illustrated; as H₃-histamine antagonists, GT-2394 and thelike are illustrated; as leptin, leptin analogues or leptin receptoragonists, LY-355101 and the like are illustrated; as cholecystokininagonists (especially CCK-A agonists), SR-146131, SSR-125180, BP-3.200,A-71623, FPL-15849, GI-248573, GW-7178, GI-181771, GW-7854, A-71378 andthe like are illustrated; and as neuropeptide Y antagonists,SR-120819-A, PD-160170, NGD-95-1, BIBP-3226, 1229-U-91, CGP-71683,BIBO-3304, CP-671906-01, J-115814 and the like are illustrated. Appetitesuppressants are used preferably for diabetes, diabetic complications,obesity, glucose metabolism disorders, hyperlipidemia,hypercholesterolemia, hypertriglyceridemia, lipid metabolism disorders,atherosclerosis, hypertension, congestive heart failure, edema,hyperuricemia or gout, and more preferably for obesity because ofstimulating or inhibiting the activities of intracerebral monoamines orbioactive peptides in central appetite regulatory system and suppressingthe appetite, leading to reduction of energy intake.

As angiotensin-converting enzyme inhibitors, captopril, enalaprimaleate, alacepril, delapril hydrochloride, ramipril, lisinopril,imidapril hydrochloride, benazepril hydrochloride, ceronaprilmonohydrate, cilazapril, sodium fosinopril, perindopril erbumine,calcium moveltipril, quinapril hydrochloride, spirapril hydrochloride,temocapril hydrochloride, trandolapril, calcium zofenopril, moexiprilhydrochloride, rentiapril and the like are illustrated.Angiotensin-converting enzyme inhibitors are preferably used fordiabetic complications or hypertension.

As neutral endopeptidase inhibitors, omapatrilat, MDL-100240,fasidotril, sampatrilat, GW-660511X, mixanpril, SA-7060, E-4030,SLV-306, ecadotril and the like are illustrated. Neutral endopeptidaseinhibitors are preferably used for diabetic complications orhypertension.

As angiotensin II receptor antagonists, candesartan cilexetil,candesartan cilexetil/hydrochlorothiazide, potassium losartan,eprosartan mesylate, valsartan, telmisartan, irbesartan, EXP-3174,L-158809, EXP-3312, olmesartan, tasosartan, KT-3-671, GA-0113, RU-64276,EMD-90423, BR-9701 and the like are illustrated. Angiotensin II receptorantagonists are preferably used for diabetic complications orhypertension.

As endothelin-converting enzyme inhibitors, CGS-31447, CGS-35066,SM-19712 and the like are illustrated; as endothelin receptorantagonists, L-749805, TBC-3214, BMS-182874, BQ-610, TA-0201, SB-215355,PD-180988, sodium sitaxsentan, BMS-193884, darusentan, TBC-3711,bosentan, sodium tezosentan, J-104132, YM-598, S-0139, SB-234551,RPR-118031A, ATZ-1993, RO-61-1790, ABT-546, enlasentan, BMS-207940 andthe like are illustrated. These drugs are preferably used for diabeticcomplications or hypertension, and more preferably for hypertension.

As diuretic agents, chlorthalidone, metolazone, cyclopenthiazide,trichloromethiazide, hydrochlorothiazide, hydroflumethiazide,benzylhydrochlorothiazide, penflutizide, methyclothiazide, indapamide,tripamide, mefruside, azosemide, etacrynic acid, torasemide, piretanide,furosemide, bumetanide, meticrane, potassium canrenoate, spironolactone,triamterene, aminophylline, cicletanine hydrochloride, LLU-α,PNU-80873A, isosorbide, D-mannitol, D-sorbitol, fructose, glycerin,acetazolamide, methazolamide, FR-179544, OPC-31260, lixivaptan,conivaptan hydrochloride and the like are illustrated. Diuretic drugsare preferably used for diabetic complications, hypertension, congestiveheart failure or edema, and more preferably for hypertension, congestiveheart failure or edema because of reducing blood pressure or improvingedema by increasing urinary excretion.

As calcium antagonists, aranidipine, efonidipine hydrochloride,nicardipine hydrochloride, barnidipine hydrochloride, benidipinehydrochloride, manidipine hydrochloride, cilnidipine, nisoldipine,nitrendipine, nifedipine, nilvadipine, felodipine, amlodipine besilate,pranidipine, lercanidipine hydrochloride, isradipine, elgodipine,azelnidipine, lacidipine, vatanidipine hydrochloride, lemildipine,diltiazem hydrochloride, clentiazem maleate, verapamil hydrochloride,S-verapamil, fasudil hydrochloride, bepridil hydrochloride, gallopamilhydrochloride and the like are illustrated; as vasodilatingantihypertensive agents, indapamide, todralazine hydrochloride,hydralazine hydrochloride, cadralazine, budralazine and the like areillustrated; as sympathetic blocking agents, amosulalol hydrochloride,terazosin hydrochloride, bunazosin hydrochloride, prazosinhydrochloride, doxazosin mesylate, propranolol hydrochloride, atenolol,metoprolol tartrate, carvedilol, nipradilol, celiprolol hydrochloride,nebivolol, betaxolol hydrochloride, pindolol, tertatolol hydrochloride,bevantolol hydrochloride, timolol maleate, carteolol hydrochloride,bisoprolol hemifumarate, bopindolol malonate, nipradilol, penbutololsulfate, acebutolol hydrochloride, tilisolol hydrochloride, nadolol,urapidil, indoramin and the like are illustrated; as centrally actingantihypertensive agents, reserpine and the like are illustrated; and asα₂-adrenoceptor agonists, clonidine hydrochloride, methyldopa, CHF-1035,guanabenz acetate, guanfacine hydrochloride, moxonidine, lofexidine,talipexole hydrochloride and the like are illustrated. These drugs arepreferably used for hypertension.

As antiplatelets agents, ticlopidine hydrochloride, dipyridamole,cilostazol, ethyl icosapentate, sarpogrelate hydrochloride, dilazepdihydrochloride, trapidil, beraprost sodium, aspirin and the like areillustrated. Antiplatelets agents are preferably used foratherosclerosis or congestive heart failure.

As uric acid synthesis inhibitors, allopurinol, oxypurinol and the likeare illustrated; as uricosuric agents, benzbromarone, probenecid and thelike are illustrated; and as urinary alkalinizers, sodium hydrogencarbonate, potassium citrate, sodium citrate and the like areillustrated. These drugs are preferably used for hyperuricemia or gout.

In case of use in combination with drugs other than SGLT2 inhibitors,for example, for diabetes, the combination with at least one member ofthe group consisting of an insulin sensitivity enhancer, a glucoseabsorption inhibitor, a biguanide, an insulin secretion enhancer,insulin or an insulin analogue, a glucagon receptor antagonist, aninsulin receptor kinase stimulant, a tripeptidyl peptidase II inhibitor,a dipeptidyl peptidase IV inhibitor, a protein tyrosine phosphatase-1Binhibitor, a glycogen phosphorylase inhibitor, a glucose-6-phosphataseinhibitor, a fructose-bisphosphatase inhibitor, a pyruvate dehydrogenaseinhibitor, a hepatic gluconeogenesis inhibitor, D-chiroinositol, aglycogen synthase kinase-3 inhibitor, glucagon-like peptide-1, aglucagon-like peptide-1 analogue, a glucagon-like peptide-1 agonist,amylin, an amylin analogue, an amylin agonist and an appetitesuppressant is preferable; the combination with at least one member ofthe group consisting of an insulin sensitivity enhancer, a glucoseabsorption inhibitor, a biguanide, an insulin secretion enhancer,insulin or an insulin analogue, a glucagon receptor antagonist, aninsulin receptor kinase stimulant, a tripeptidyl peptidase II inhibitor,a dipeptidyl peptidase IV inhibitor, a protein tyrosine phosphatase-1Binhibitor, a glycogen phosphorylase inhibitor, a glucose-6-phosphataseinhibitor, a fructose-bisphosphatase inhibitor, a pyruvate dehydrogenaseinhibitor, a hepatic gluconeogenesis inhibitor, D-chiroinositol, aglycogen synthase kinase-3 inhibitor, glucagon-like peptide-1, aglucagon-like peptide-1 analogue, a glucagon-like peptide-1 agonist,amylin, an amylin analogue and an amylin agonist is more preferable; andthe combination with at least one member of the group consisting of aninsulin sensitivity enhancer, a glucose absorption inhibitor, abiguanide, an insulin secretion enhancer and insulin or an insulinanalogue is most preferable. Similarly, for diabetic complications, thecombination with at least one member of the group consisting of aninsulin sensitivity enhancer, a glucose absorption inhibitor, abiguanide, an insulin secretion enhancer, insulin or an insulinanalogue, a glucagon receptor antagonist, an insulin receptor kinasestimulant, a tripeptidyl peptidase II inhibitor, a dipeptidyl peptidaseIV inhibitor, a protein tyrosine phosphatase-1B inhibitor, a glycogenphosphorylase inhibitor, a glucose-6-phosphatase inhibitor, afructose-bisphosphatase inhibitor, a pyruvate dehydrogenase inhibitor, ahepatic gluconeogenesis inhibitor, D-chiroinositol, glycogen synthasekinase-3 inhibitors, glucagon-like peptide-1, a glucagon-like peptide-1analogue, a glucagon-like peptide-1 agonist, amylin, an amylin analogue,an amylin agonist, an aldose reductase inhibitor, an advanced glycationend products formation inhibitor, a protein kinase C inhibitor, aγ-aminobutyric acid antagonist, a sodium channel antagonist, atranscript factor NF-κB inhibitor, a lipid peroxidase inhibitor, anN-acetylated-α-linked-acid-dipeptidase inhibitor, insulin-like growthfactor-I, platelet-derived growth factor, a platelet derived growthfactor analogue, epidermal growth factor, nerve growth factor, acarnitine derivative, uridine, 5-hydroxy-1-methylhydantoin, EGB-761,bimoclomol, sulodexide, Y-128, an angiotensin-converting enzymeinhibitor, a neutral endopeptidase inhibitor, an angiotensin II receptorantagonist, an endothelin-converting enzyme inhibitor, an endothelinreceptor antagonist and a diuretic agent is preferable; and thecombination with at least one member of the group consisting of analdose reductase inhibitor, an angiotensin-converting enzyme inhibitor,a neutral endopeptidase inhibitor and an angiotensin II receptorantagonist is more preferable. Furthermore, for obesity, the combinationwith at least one member of the group consisting of an insulinsensitivity enhancer, a glucose absorption inhibitor, a biguanide, aninsulin secretion enhancer, insulin or an insulin analogue, a glucagonreceptor antagonist, an insulin receptor kinase stimulant, a tripeptidylpeptidase II inhibitor, a dipeptidyl peptidase IV inhibitor, a proteintyrosine phosphatase-1B inhibitor, a glycogen phosphorylase inhibitor, aglucose-6-phosphatase inhibitor, a fructose-bisphosphatase inhibitor, apyruvate dehydrogenase inhibitor, a hepatic gluconeogenesis inhibitor,D-chiroinositol, a glycogen synthase kinase-3 inhibitor, glucagon-likepeptide-1, a glucagon-like peptide-1 analogue, a glucagon-like peptide-1agonist, amylin, an amylin analogue, an amylin agonist, aβ₃-adrenoceptor agonist and an appetite suppressant is preferable; andthe combination with at least one member of the group consisting of aβ₃-adrenoceptor agonist and an appetite suppressant is more preferable.

When the pharmaceutical compositions of the present invention areemployed in the practical treatment,various dosage forms are useddepending on their uses. As examples of the dosage forms, powders,granules, fine granules, dry syrups, tablets, capsules, injections,solutions, ointments, suppositories, poultices and the like areillustrated, which are orally or parenterally administered.

These pharmaceutical compositions can be prepared by admixing with or bydiluting with and dissolving in an appropriate pharmaceutical additivesuch as excipients, disintegrators, binders, lubricants, diluents,buffers, isotonicities, antiseptics, moistening agents, emulsifiers,dispersing agents, stabilizing agents, dissolving aids and the like, andformulating the mixture in accordance with pharmaceutically conventionalmethods depending on their dosage forms. In case of the use of thecompound of the present invention in combination with the drugs otherthan SGLT2 inhibitors, they can be prepared by formulating each activeingredient together or individually.

When the pharmaceutical compositions of the present invention areemployed in the practical treatment, the dosage of a nitrogen-containingheterocyclic derivative represented by the above general formula (I) ora pharmaceutically acceptable salt thereof, or a prodrug thereof as theactive ingredient is appropriately decided depending on the age, sex,body weight and degree of symptoms and treatment of each patient, whichis approximately within the range of from 0.1 to 1,000 mg per day peradult human in the case of oral administration and approximately withinthe range of from 0.01 to 300 mg per day per adult human in the case ofparenteral administration, and the daily dose can be divided into one toseveral doses per day and administered suitably. Also, in case of theuse of the compound of the present invention in combination with thedrugs other than SGLT2 inhibitors, the dosage of the compound of thepresent invention can be decreased depending on the dosage of the drugsother than SGLT2 inhibitors.

EXAMPLES

The present invention is further illustrated in more detail by way ofthe following Examples and Test Examples. However, the present inventionis not limited thereto.

Example 1

Process 1

2-Benzyloxy-4,6-dimethylpyridin-3-yl 3-fluoro-4-methyl-phenyl methanol

A Grignard reagent was prepared in the usual way using1-bromo-3-fluoro-4-methylbenzene (0.53 g), Magnesium (0.069 g), acatalytic amount of iodine and tetrahydrofuran (5 mL). To atetrahydrofuran solution of the Grignard reagent was added a solution of2-benzyloxy-3-formyl-4,6-dimethylpyridene (0.34 g) in tetrahydrofuran (5mL) at 0° C. After the reaction mixture was stirred at room temperaturefor 1 hour, a saturated aqueous ammonium solution and water were added,and the mixture was extracted with diethyl ether. The organic layer waswashed with brine and dried over anhydrous magnesium sulfate, and thesolvent was removed under reduced pressure. The residue was purified bycolumn chromatography on silica gel (hexane/ethyl acetate=6/1) to givethe title compound (0.39 g).

Process 2

3-(3-Fluoro-4-methylbenzyl)-4,6-dimethyl-1H-pyridin-2-one

To a solution of 2-benzyloxy-4,6-dimethylpyridin-3-yl3-fluoro-4-methylphenyl methanol (0.39 g) in ethanol (10 mL) was added acatalytic amount of palladium carbon powder, and the mixture was stirredat room temperature under a hydrogen atmosphere overnight. After theinsoluble material was removed by filtration, the solvent of thefiltrate was removed to give the title compound (0.22 g).

¹H-NMR (CDCl₃) δ ppm: 2.14 (3H, s), 2.20 (3H, d, J=1.1 Hz), 2.22 (3H,s), 3.88 (2H, s), 5.86 (1H, s), 6.85-6.95 (2H, m), 6.95-7.10 (1H, m)

Process 3

2-(2,3,4,6-Tetra-O-acethyl-β-D-glucopyranosyloxy)-3-(3-fluoro-4-methylbenzyl)-4,6-dimethylpyridine

To a solution of3-(3-fluoro-4-methylbenzyl)-4,6-dimethyl-1H-pyridin-2-one (0.08 g) andacetobromo-α-D-glucose (0.15 g) in dichloromethane (2 mL) was addedsilver carbonate (0.090 g), and the mixture was stirred at roomtemperature overnight in the shade. The insoluble material was removedby filtration, and the filtrate was purified by column chromatography onaminopropylated silica gel (dichloromethane) to give the title compound(0.17 g).

¹H-NMR (CDCl₃) δ ppm: 1.78 (3H, s), 2.00 (3H, s), 2.04 (3H, s), 2.04(3H, s), 2.16 (3H, s), 2.17-2.20 (3H, m), 2.38 (3H, s), 3.79 (1H, d,J=15.7 Hz), 3.93 (1H, ddd, J=2.5, 4.7, 10.1 Hz), 3.97 (1H, d, J=15.7Hz), 4.13 (1H, dd, J=2.5; 12.3 Hz), 4.25 (1H, dd, J=4.7, 12.3 Hz),5.10-5.20 (1H, m), 5.25-5.40 (2H, m), 6.15-6.25 (1H, m), 6.60-6.70 (2H,m), 6.75-6.80 (1H, m), 6.95-7.05 (1H, m)

Process 4

2-(β-D-Glucopyranosyloxy)-3-(3-fluoro-4-methylbenzyl)-4,6-dimethylpyridine

To a solution of2-(2,3,4,6-tetra-O-acetyl-β-D-gluco-pyranosyloxy)-3-(3-fluoro-4-methylbenzyl)-4,6-dimethyl-pyridine(0.17 g) in methanol (5 mL) was added sodium methoxide (28% methanolsolution, 0.028 mL), and the mixture was stirred at room temperature for1 hour. The solvent of the reaction mixture was removed, and the residuewas purified by column chromatography on silica gel(dichloromethane/methanol=10/1) to give the title compound (0.081 g).

¹H-NMR (CD₃OD) δ ppm: 2.17 (6H, s), 2.36 (3H, s), 3.30-3.55 (4H, m),3.67 (1H, dd, J=5.3, 11.9 Hz), 3.84 (1H, dd, J=2.4, 11.9 Hz), 3.94 (1H,d, J=15.6 Hz), 4.06 (1H, d, J=15.6 Hz), 5.85-6.00 (1H, m), 6.70-6.80(1H, m), 6.80-6.95 (2H, m), 7.00-7.10 (1H, m)

Examples 2-3

The compounds described in Table 1 were prepared in a similar manner tothat described in Example 1 using corresponding starting materials.

TABLE 1 Example number Chemical structure ¹H-NMR (CD₃OD) δ ppm: Example2

2.29 (3H, s), 3.35-3.60 (4H, m), 3.68 (1H, dd, J=5.0. 12.0Hz), 3.84 (1H,d, J=12.0Hz), 3.92(1H, d, J=15.4Hz), 3.96 (1H, d, J=15.4Hz), 5.80-5.95(1H, m), 6.85-7.20 (5H, m), 7.30-7.45 (1H, m), 7.90-8.05 (1H, m) Example3

2.20 (3H, s), 3.35-3.60 (4H, m), 3.70 (1H, dd, 5.0, 12.0Hz), 3.85 (1H,dd, J=2.1, 12.0Hz), 3.97 (1H, d, J=16.7Hz), 4.02 (1H, d, J=16.7Hz),5.85-5.95 (1H, m), 6.80-6.95 (1H, m), 7.00-7.25 (5H, m), 7.90-8.05 (1H,m)

Test Example 1

Assay for Inhibitory Effects on Human SGLT2 Activity

1) Cloning and Construction of the Vector Expressing Human SGLT2

The cDNA library was prepared for PCR amplification by reversetranscription from total RNA deprived from human kidney (Ori gene) usingoligo-dT as a primer. Using this cDNA library as a template, the basesequence coding 2 to 2039 bp of human SGLT2 (ACCESSION: M95549, M95299),which was reported by R. G. Wells et al., was amplified by PCR methodand inserted into the multi-cloning site of pcDNA3.1(−) (Invitrogen).The DNA sequence inserted was perfectly matched to the previouslyreported sequence.

2) Establishment of Cell Line Stably Expressing Human SGLT2

The expression vector of human SGLT2 was digested by Sca I into a linearDNA. The linear DNA was transfected into CHO-K1 cells by means oflipofection (Effectene Transfection Reagent: QIAGEN). Neomycin resistantcell lines were obtained by culture in the medium containing 1 mg/mL ofG418 (LIFE TECHNOLOGIES), and then the activity against the uptake ofmethyl-α-D-gluco-pyranoside was measured by the method described below.The cell line, which showed the greatest uptake activity, was selectedand designated as CS2-5E. Afterward, CS2-5E cells were cultured in thepresence of G418 at 200 μg/mL.

3) Measurement of the Inhibitory Activity Against the Uptake ofmethyl-α-D-glucopyranoside (α-MG)

CS2-5E cells were seeded into a 96-well culture plate at a density of3×10⁴ cells/well and cultured for 2 days, and were used in the uptakeassay. A mixture of non-radiolabeled (Sigma) and ¹⁴C-labeled α-MG(Amersham Pharmcia Biotec) was added to the uptake buffer (pH 7.4;containing 140 mM sodium chloride, 2 mM potassium chloride, 1 mM calciumchloride, 1 mM magnesium chloride, 10 mM2-[4-(2-hydroxyethyl)-1-piperazinyl]ethane sulfonic acid, and 5 mM tris(hydroxymethyl)aminomethane) at the final concentration of 1 mM. A testcompound was dissolved in dimethyl sulfoxide, and then appropriatelydiluted with distilled water. The test compound solution was added tothe uptake buffer containing 1 mM α-MG, and designated as a measurementbuffer. For the control group, the measurement buffer without any testcompound was prepared. For measuring the basal uptake, a basal uptakemeasurement buffer which contains 140 mM chorine chloride instead ofsodium chloride was prepared. After removing the culture medium ofcells, 180 μL of the pre-treatment buffer (the basal uptake bufferwithout α-MG) was added to each well and incubated at 37° C. for 10minutes. After repeating once the same treatment, the pre-treatmentbuffer was removed. To each well was added 75 μL of the measurementbuffer or the basal uptake buffer was added and incubated at 37° C.After 1 hour, the measurement buffer was removed, and cells were washedtwice with 180 μL per well of the washing buffer (the basal uptakebuffer containing 10 mM non-labeled α-MG). The cells were solubilized by75 μL per well of 0.2 mol/L sodium hydroxide. The cell lysates weretransferred into PicoPlates (Packard), and then added 150 μL ofMicroScint-40 (Packard) and mixed. Radioactivity was measured by meansof scintillation counter (Packard). One hundred % was set to thedifference between the uptake in the control group and the basal uptake,and the percentage of the uptake of methyl α-D-glucopyranoside at eachdrug concentration were calculated. The drug concentration, at which 50%uptake of methyl α-D-glucopyranoside was inhibited (IC₅₀ value), wascalculated using logit plot. The results were shown in Table 2.

TABLE 2 Test compound IC₅₀ (nM) Example 1 3

INDUSTRIAL APPLICABILITY

The nitrogen-containing heterocyclic derivatives represented by theabove general formula (I) of the present invention, pharmaceuticallyacceptable salts thereof and prodrugs thereof show an excellenthypoglycemic effect by excreting excess glucose into the urine throughpreventing the reabsorption of glucose at the kidney because theyexhibit an excellent inhibitory activity in human SGLT2. The presentinvention can provide drugs for the prevention or treatment of a diseaseassociated with hyperglycemia such as diabetes, diabetic complications,obesity or the like.

1. A nitrogen-containing heterocyclic derivative represented by thegeneral formula:

wherein X¹ represents N or CR¹; X² represents N or CR²; X³ represents Nor CR³; X⁴ represents N or CR⁴; and with the proviso that one or two ofX¹, X², X³ and X⁴ represent N; R represents a C₃₋₈ cycloalkyl groupwhich may have the same or different 1 to 3 groups selected from thefollowing substituent group (A), a C₆₋₁₀ aryl group which may have thesame or different 1 to 3 groups selected from the following substituentgroup (B), a C₂₋₉ heterocycloalkyl group which may have the same ordifferent 1 to 3 groups selected from the following substituent group(A),or a C₁₋₉ heteroaryl group which may have the same or different 1 to3 groups selected from the following substituent group (B); R¹ to R⁴ arethe same or different, independently represents a hydrogen atom or agroup selected from the following substituent group (D); substituentgroup (A) consists of a halogen atom, a nitro group, a cyano group, anoxo group, -G¹, -OG², -SG², —N(G²)₂, —C(═O)G², —C(═O)OG²—C(═O)N(G²)₂,—S(═O)₂G², —S(═O)₂OG², —S(═O)₂N(G²)₂, —S(═O)G¹, —OC(═O)G¹,—OC(═O)N(G²)₂, —NHC(═O)G², —OS(═O)₂G¹, —NHS(═O)₂G¹ and —C(═O)NHS(═O)₂G¹;substituent group(B) consists of a halogen atom, a nitro group, a cyanogroup, -G¹, —OG², —SG², —N(G²)₂, -G³OG⁴, -G³N(G⁴)₂, -C(═O)G², -C(═O)OG²,-C(═O)N(G²)₂, —S(═O)₂G², —S(═O)₂OG², —S(═O)₂N(G²)₂, —S(═O)G¹, —OC(═O)G¹,—OC(═O)N(G²)₂, —NHC(═O)G², —OS(═O)₂G¹, —NHS(═O)₂G¹ and —C(═O)NHS(═O)₂G¹in the substituent group (A) and/or (B), G¹ represents a C₁₋₆ alkylgroup which may have the same or different 1 to 3 groups selected fromthe following substituent group (C), a C₂₋₆ alkenyl group which may havethe same or different 1 to 3 groups selected from the followingsubstituent group (C), a C₂₋₆ alkynyl group which may have the same ordifferent 1 to 3 groups selected from the following substituent group(C), a C₃₋₈ cycloalkyl group which may have the same or different 1 to 3groups selected from the following substituent group (C), a C₆₋₁₀ arylgroup which may have the same or different 1 to 3 groups selected fromthe following substituent group (D), a C₂₋₉ heterocycloalkyl group whichmay have the same or different 1 to 3 groups selected from the followingsubstituent group (C), a C₁₋₉ heteroaryl group which may have the sameor different 1 to 3 groups selected from the following substituent group(D); G² represents a hydrogen atom, a C₁₋₆ alkyl group which may havethe same or different 1 to 3 groups selected from the followingsubstituent group (C), a C₂₋₆ alkenyl group which may have the same ordifferent 1 to 3 groups selected from the following substituent group(C), a C₂₋₆ alkynyl group which may have the same or different 1 to 3groups selected from the following substituent group (C), a C₃₋₈cycloalkyl group which may have the same or different 1 to 3 groupsselected from the following substituent group (C), a C₆₋₁₀ aryl groupwhich may have the same or different 1 to 3 groups selected from thefollowing substituent group (D), a C₂₋₉ heterocycloalkyl group which mayhave the same or different 1 to 3 groups selected from the followingsubstituent group (D), a C₁₋₉ heteroaryl group which may have the sameor different 1 to 3 groups selected from the following substituent group(D), and with the proviso that G² are the same or different when thereare more than one G² in the substituents; G³ represents a C₁₋₆ alkylgroup; G⁴ represents a C₁₋₆ alkyl group which may have the same ordifferent 1 to 3 groups selected from the following substituent group(C), and with the proviso that G⁴ are the same or different when thereare more than one G⁴ in the substituents; substituent group (C) consistsof a halogen atom, a nitro group, a cyano group, an oxo group, -G⁵,—OG⁶, —SG⁶, —N(G⁶)₂, —C(═O)G⁶, —C(═O)OG⁶, —C(═O)N(G⁶)₂, —S(═O)₂G⁶,—S(═O)₂OG⁶, —S(═O)₂N(G⁶)₂, —S(═O)G⁵, —OC(═O)G⁵, —OC(═O)N(G⁶)₂,—NHC(═O)G⁶, —OS(═O)₂G⁵, —NHS(═O)₂G⁵ and —C(═O)NHS(═O)₂G⁵; substituentgroup (D) consists of a halogen atom, a nitro group, a cyano group, -G⁵,—OG⁶, -SG⁶, —N(G⁶)₂, —C(═O)G⁶, —C(═O)OG⁶, —C(═O)N(G⁶)₂, —S(═O)₂G⁶,—S(═O)₂OG⁶, —S(═O)₂N(G⁶)₂, —S(═O)G⁵, —OC(═O)G⁵, —OC(═O)N(G⁶)₂,—NHC(═O)G⁶, —OS(═O)₂G⁵, —NHS(═O)₂G⁵ and —C(═O)NHS(═O)₂G⁵ in thesubstituent group (C) and/or (D), G⁵ represents a C₁₋₆ alkyl group, aHO—C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₂₋₆ alkynyl group, a C₃₋₈cycloalkyl group, a C₆₋₁₀ aryl group, a C₂₋₉ heterocycloalkyl group or aC₁₋₉ heteroaryl group; G⁶ represents a hydrogen atom, a C₁₋₆ alkylgroup, a C₂₋₆ alkenyl group, a C₂₋₆ alkynyl group, a C₃₋₈ cycloalkylgroup, a C₆₋₁₀ aryl group, a C₂₋₉ heterocycloalkyl group or a C₁₋₉heteroaryl group, and with the proviso that G⁶ are the same or differentwhen there are more than one G⁶ in the substituents and with the provisothat when X¹ and X³ independently represent N or CH; X² represents N orCR², wherein R² represents a hydrogen atom, a halogen atom, a C₁₋₆ alkylgroup, a C₃₋₈ cycloalkyl group, —O—C₁₋₆ alkyl, an amino group, —NH—C₂₋₇acyl, —NH—C₁₋₆ alkyl or —N(C₁₋₆ alkyl)₂; and when X⁴ represents N orCR⁴, wherein R⁴ represents a hydrogen atom or a C₁₋₆ alkyl group, Rrepresents the above-defined group except for the following substituent:

wherein Z represents a hydrogen atom, a halogen atom, a C₁₋₆ alkyl groupwhich may have a substituent selected from the following substituentgroup (α), —O—C₁₋₆ alkyl which may have a substituent selected from thefollowing substituent group (β), —S—C₁₋₆ alkyl which may have asubstituent selected from the following substituent group (β) or a C₃₋₈cycloalkyl group; substituent group (α) consists of a halogen atom, ahydroxy group and —O—C₁₋₆ alkyl; and substituent group (β) consists of ahydroxy group and —O—C₁₋₆ alkyl, or a pharmaceutically acceptable saltthereof, or a prodrug thereof.
 2. A nitrogen-containing heterocyclicderivative as claimed in claim 1 wherein R represents a phenyl groupwhich may have the same or different 1 to 3 groups selected from thefollowing substituent group (B), or a pharmaceutically acceptable saltthereof, or a prodrug thereof substituent group (B) consists of ahalogen atom, a nitro group, a cyano group, -G¹, —OG², —SG², —N(G²)₂,-G³OG⁴, -G³N(G⁴)₂, —C(═O)G², —C(═O)OG², —C(═O)N(G²)₂, —S(═O)₂G²,—S(═O)₂OG², —S(═O)₂N(G²)₂, —S(═O)G¹, —OC(═O)G¹, —OC(═O)N(G²)₂,—NHC(═O)G², —OS(═O)₂G¹, —NHS(═O)₂G¹ and —C(═O)NHS(═O)₂G¹ in thesubstituent group (B), G¹ represents a C₁₋₆ alkyl group which may havethe same or different 1 to 3 groups selected from the followingsubstituent group (C), a C₂₋₆ alkenyl group which may have the same ordifferent 1 to 3 groups selected from the following substituent group(C), a C₂₋₆ alkynyl group which may have the same or different 1 to 3groups selected from the following substituent group (C), a C₃₋₈cycloalkyl group which may have the same or different 1 to 3 groupsselected from the following substituent group (C), a C₆₋₁₀ aryl groupwhich may have the same or different 1 to 3 groups selected from thefollowing substituent group (D), a C₂₋₉ heterocycloalkyl group which mayhave the same or different 1 to 3 groups selected from the followingsubstituent group (C), a C₁₋₉ heteroaryl group which may have the sameor different 1 to 3 groups selected from the following substituent group(D); G²represents a hydrogen atom, a C₁₋₆ alkyl group which may have thesame or different 1 to 3 groups selected from the following substituentgroup (C), a C₂₋₆ alkenyl group which may have the same or different 1to 3 groups selected from the following substituent group (C), a C₂₋₆alkynyl group which may have the same or different 1 to 3 groupsselected from the following substituent group(C), a C₃₋₈ cycloalkylgroup which may have the same or different 1 to 3 groups selected fromthe following substituent group (C), a C₆₋₁₀ aryl group which may havethe same or different 1 to 3 groups selected from the followingsubstituent group (D), a C₂₋₉ heterocycloalkyl group which may have thesame or different 1 to 3 groups selected from the following substituentgroup (D), a C₁₋₉ heterooalkyl group which may have the same ordifferent 1 to 3 groups selected from the following substituent group(D), and with the proviso that G² are the same or different when thereare more than one G² in the substituents; G³ represents a C₁₋₆ alkylgroup; G⁴ represents a C₁₋₆ alkyl group which may have the same ordifferent 1 to 3 groups selected from the following substituent group(C), and with the proviso that G⁴ are the same or different when thereare more than one G⁴ in the substituents; substituent group (C) consistsof a halogen atom, a nitro group, a cyano group, an oxo group, -G⁵,—OG⁶, —SG⁶, —N(G⁶)₂, —C(═O)G⁶, —C(═O)OG⁶, —C(═O)N(G⁶)₂, —S(═O)₂G⁶,—S(═O)₂OG⁶, —S(═O)₂N(G⁶)₂,—S(═O)G⁵, —OC(═O)G⁵, —OC(═O)N(G⁶)₂,—NHC(═O)G⁶, —OS(═O)₂G⁵, —NHS(═O)₂G⁵ and —C(═O)NHS(═O)₂G⁵; andsubstituent group (D) consists of a halogen atom, a nitro group, a cyanogroup, -G⁵, —OG⁶, —SG⁶, —N(G⁶)₂, —C(═O)G⁶, —C(═O)OG⁶, —C(═O)N(G⁶)₂,—S(═O)₂G⁶, —S(═O)₂OG⁶, —S(═O)₂N(G⁶)₂, —S(═O)G⁵, —OC(═O)G⁵,—OC(═O)N(G⁶)₂, —NHC(═O)G⁶, —OS(═O)₂G⁵, —NHS(═O)₂G⁵ and —C(═O)NHS(═O)₂G⁵in the substituent group (C) and/or (D), G⁵ represents a C₁₋₆ alkylgroup, a C₂₋₆ alkenyl group, a C₂₋₆ alkynyl group, a C₃₋₈ cycloalkylgroup, a C₆₋₁₀ aryl group, a C₂₋₉ heterocycloalkyl group or a C₁₋₉heteroaryl group; and G⁶represents a hydrogen atom, a C₁₋₆ alkyl group,a C₂₋₆ alkenyl group, a C₂₋₆ alkynyl group, a C₃₋₈ cycloalkyl group, aC₆₋₁₀ aryl group, a C₂₋₉ heterocycloalkyl group or a C₁₋₉ heteroarylgroup, and with the proviso that G⁶ are the same or different when thereare more than one G⁶ in the substituents.
 3. A pharmaceuticalcomposition comprising as an active ingredient a nitrogen-containingheterocyclic derivative as claimed in claim 1 or 2, or apharmaceutically acceptable salt thereof, or a prodrug thereof.
 4. Apharmaceutical composition as claimed in claim 3 wherein the compositionis a human SGLT2 inhibitor.
 5. A method for the treatment of a diseaseassociated with hyperglycemia, which comprises administering aneffective amount of a nitrogen-containing heterocyclic derivative asclaimed in claim 1 or 2, or a pharmaceutically acceptable salt thereof,or a prodrug thereof.
 6. A pharmaceutical combination which comprises(A) a nitrogen-containing heterocyclic derivative as claimed in claim 1or 2, or a pharmaceutically acceptable salt thereof, or a prodrugthereof, and (B) at least one member selected from the group consistingof an insulin sensitivity enhancer, a glucose absorption inhibitor, abiguanide, an insulin secretion enhancer, insulin or an insulinanalogue, a glucagon receptor antagonist, an insulin receptor kinasestimulant, a tripeptidyl peptidase II inhibitor, a dipeptidyl peptidaseIV inhibitor, a protein tyrosine phosphatase-1 B inhibitor, a glycogenphosphorylase inhibitor, a glucose-6-phosphatase inhibitor, afructose-bisphosphatase inhibitor, a pyruvate dehydrogenase inhibitor, ahepatic gluconeogenesis inhibitor, D-chiroinsitol, a glycogen synthasekinase-3 inhibitor, glucagon-like peptide-1, a glucagon-like peptide-1analogue, a glucagon-like peptide-1 agonist, amylin, an amylin analogue,an amylin agonist, an aldose reductase inhibitor, an advanced glycationend products formation inhibitor, a protein kinase C inhibitor, aγ-aminobutyric acid receptor antagonist, a sodium channel antagonist, atranscript factor NF-κB inhibitor, a lipid peroxidase inhibitor, anN-acetylated-α-linked-acid-dipeptidase inhibitor, insulin-like growthfactor-I, platelet-derived growth factor, a platelet-derived growthfactor analogue, epidermal growth factor, nerve growth factor, acarnitine derivative, uridine, 5-hydroxy-1-methylhydantoin, EGB-761,bimoclomol, sulodexide, Y-128, a hydroxymethyl-glutaryl coenzyme Areductase inhibitor, a fibric acid derivative, a β₃-adrenoceptoragonist, an acyl-coenzyme A: cholesterol acyltransferase inhibitor,probcol, a thyroid hormone receptor agonist, a cholesterol absorptioninhibitor, a lipase inhibitor, a microsomal triglyceride transferprotein inhibitor, a lipoxygenase inhibitor, a carnitinepalmitoyl-transferase inhibitor, a squalene synthase inhibitor, alow-density lipoprotein receptor enhancer, a nicotinic acid derivative,a bile acid sequestrant, a sodium/bile acid cotransporter inhibitor, acholesterol ester transfer protein inhibitor, an appetite suppressant,an angiotensin-converting enzyme inhibitor, a neutral endopeptidaseinhibitor, an angiotensin II receptor antagonist, anendothelin-converting enzyme inhibitor, an endothelin receptorantagonist, a diuretic agent, a calcium antagonist, a vasodilatingantihypertensive agent, a sympathetic blocking agent, a centrally actingantihypertensive agent, an α₂-adrenoceptor agonist, an antiplateletsagent, a uric acid synthesis inhibitor, a uricosuric agent and a urinaryalkalinizer.
 7. A pharmaceutical combination as claimed in claim 6 forthe treatment of a disease associated with hyperglycemia.
 8. Apharmaceutical combination as claimed in claim 7 wherein a component (B)is at least one member selected from the group consisting of an insulinsensitivity enhancer, a glucose absorption inhibitor, a biguanide, aninsulin secretion enhancer, insulin or an insulin analogue, a glucagonreceptor antagonist, an insulin receptor kinase stimulant, a tripeptidylpeptidase II inhibitor, a dipeptidyl peptidase IV inhibitor, a proteintyrosine phosphatase-1B inhibitor, a glycogen phosphorylase inhibitor, aglucose-6-phosphatase inhibitor, a fructose-bisphosphatase inhibitor, apyruvate dehydrogenase inhibitor, a hepatic gluconeogenesis inhibitor,D-chiroinsitol, a glycogen synthase kinase-3inhibitor, glucagon-likepeptide-1, a glucagon-like peptide-1 analogue, a glucagon-like peptide-1agonist, amylin, an amylin analogue, an amylin agonist and an appetitesuppressant, and the disease associated with hyperglycemia is diabetes.9. A pharmaceutical combination as claimed in claim 8 wherein acomponent (B) is at least one member selected from the group consistingof an insulin sensitivity enhancer, a glucose absorption inhibitor, abiguanide, an insulin secretion enhancer, insulin or an insulinanalogue, a glucagon receptor antagonist, an insulin receptor kinasestimulant, a tripeptidyl peptidase II inhibitor, a dipeptidyl peptidaseIV inhibitor, a protein tyrosine phosphatase-1B inhibitor, a glycogenphosphorylase inhibitor, a glucose-6-phosphatase inhibitor, afructose-bisphosphatase inhibitor, a pyruvate dehydrogenase inhibitor, ahepatic gluconeogenesis inhibitor, D-chiroinsitol, a glycogen synthasekinase-3 inhibitor, glucagon-like peptide-1, a glucagon-like peptide-1analogue, a glucagon-like peptide-1 agonist, amylin, an amylin analogueand an amylin agonist.
 10. A pharmaceutical combination as claimed inclaim 9 wherein a component (B) is at least one member selected from thegroup consisting of an insulin sensitivity enhancer, a glucoseabsorption inhibitor, a biguanide, an insulin secretion enhancer andinsulin or an insulin analogue.
 11. A pharmaceutical combination asclaimed in claim 7 wherein a component (B) is at least one memberselected from the group consisting of an insulin sensitivity enhancer, aglucose absorption inhibitor, a biguanide, an insulin secretionenhancer, insulin or an insulin analogue, a glucagon receptorantagonist, an insulin receptor kinase stimulant, a tripeptidylpeptidase II inhibitor, a dipeptidyl peptidase IV inhibitor, a proteintyrosine phosphatase-1B inhibitor, a glycogen phosphorylase inhibitor, aglucose-6-phosphatase inhibitor, a fructose-bisphosphatase inhibitor, apyruvate dehydrogenase inhibitor, a hepatic gluconeogenesis inhibitor,D-chiroinsitol, glycogen synthase kinase-3 inhibitors, glucagon-likepeptide-1, a glucagon-like peptide-1 analogue, a glucagon-like peptide-1agonist, amylin, an amylin analogue, an amylin agonist, an aldosereductase inhibitor, an advanced glycation end products formationinhibitor, a protein kinase C inhibitor, a γ-aminobutyric acidantagonist, a sodium channel antagonist, a transcript factor NF-κBinhibitor, a lipid peroxidase inhibitor, anN-acetylated-α-linked-acid-dipeptidase inhibitor, insulin-like growthfactor-I, platelet-derived growth factor, a platelet derived growthfactor analogue, epidermal growth factor, nerve growth factor, acarnitine derivative, uridine, 5-hydroxy-1-methylhydantoin, EGB-761,bimoclomol, sulodexide, Y-128, an angiotensin-converting enzymeinhibitor, a neutral endopeptidase inhibitor, an angiotensin II receptorantagonist, an endothelin-converting enzyme inhibitor, an endothelinreceptor antagonist and a diuretic agent, and the disease associatedwith hyperglycemia is diabetic complications.
 12. A pharmaceuticalcombination as claimed in claim 11 wherein a component (B) is at leastone member selected from the group consisting of an aldose reductaseinhibitor, an angiotensin-converting enzyme inhibitor, a neutralendopeptidase inhibitor and an angiotensin II receptor antagonist.
 13. Apharmaceutical combination as claimed in claim 7 wherein a component (B)is at least one member selected from the group consisting of an insulinsensitivity enhancer, a glucose absorption inhibitor, a biguanide, aninsulin secretion enhancer, an insulin analogue, a glucagon receptorantagonist, an insulin receptor kinase stimulant, a tripeptidylpeptidase II inhibitor, a dipeptidyl peptidase IV inhibitor, a proteintyrosine phosphatase-1B inhibitor, a glycogen phosphorylase inhibitor, aglucose-6-phosphatase inhibitor, a fructose-bisphosphatase inhibitor, apyruvate dehydrogenase inhibitor, a hepatic gluconeogenesis inhibitor,D-chiroinsitol, a glycogen synthase kinase-3 inhibitor, glucagon-likepeptide-1, a glucagon-like peptide-1 analogue, a glucagon-like peptide-1agonist, amylin, an amylin analogue, an amylin agonist, aβ₃-adrenoceptor agonist and an appetite suppressant, and the diseaseassociated with hyperglycemia is obesity.
 14. A pharmaceuticalcombination as claimed in claim 13 wherein a component (B) is at leastone member selected from the group consisting of a β₃-adrenoceptoragonist and an appetite suppressant.
 15. A pharmaceutical combination asclaimed in claim 14 wherein the appetite suppressant is a drug selectedfrom the group consisting of a monoamine reuptake inhibitor, a serotoninreuptake inhibitor, a serotonin releasing stimulant, a serotoninagonist, a noradrenaline reuptake inhibitor, a noradrenaline releasingstimulant, an α₁-adrenoceptor agonist, a β₂-adrenoceptor agonist, adopamine agonist, a cannabinoid receptor antagonist, a γ-aminobutyricacid receptor antagonist, a H₃-histamine antagonist, L-histidine,leptin, a leptin analogue, a leptin receptor agonist, a melanocortinreceptor agonist, α-melanocyte stimulating hormone, cocaine-andamphetamine-regulated transcript, mahogany protein, an enterostatinagonist, calcitonin, calcitonin-gene-related peptide, bombesin, acholecystokinin agonist, corticotropin-releasing hormone, acorticotropin-releasing hormone analogue, a corticotropin-releasinghormone agonist, urocortin, somatostatin, a somatostatin analogue, asomatostatin receptor agonist, pituitary adenylate cyclase-activatingpeptide, brain-derived neurotrophic factor, ciliary neurotrophic factor,thyrotropin-releasing hormone, neurotensin, sauvagine, a neuropeptide Yantagonist, an opioid peptide antagonist, a galanin antagonist, amelanin-concentrating hormone receptor antagonist, an agouti-relatedprotein inhibitor and an orexin receptor antagonist.
 16. A method forthe treatment of a disease associated with hyperglycemia, whichcomprises administering an effective amount of (A) a nitrogen-containingheterocyclic derivative as claimed in claim 1 or 2, or apharmaceutically acceptable salt thereof, or a prodrug thereof, incombination with (B) at least one member selected from the groupconsisting of an insulin sensitivity enhancer, a glucose absorptioninhibitor, a biguanide, an insulin secretion enhancer, insulin or aninsulin analogue, a glucagon receptor antagonist, an insulin receptorkinase stimulant, a tripeptidyl peptidase II inhibitor, a dipeptidylpeptidase IV inhibitor, a protein tyrosine phosphatase-1B inhibitor, aglycogen phosphorylase inhibitor, a glucose-6-phosphatase inhibitor, afructose-bisphosphatase inhibitor, a pyruvate dehydrogenase inhibitor, ahepatic gluconeogenesis inhibitor, D-chiroinsitol, a glycogen synthasekinase-3 inhibitor, glucagon-like peptide-1, a glucagon-like peptide-1analogue, a glucagon-like peptide-1 agonist, amylin, an amylin analogue,an amylin agonist, an aldose reductase inhibitor, an advanced glycationend products formation inhibitor, a protein kinase C inhibitor, aγ-aminobutyric acid receptor antagonist, a sodium channel antagonist, atranscript factor NF-κB inhibitor, a lipid peroxidase inhibitor, anN-acetylated-α-linked-acid-dipeptidase inhibitor, insulin-like growthfactor-I, platelet-derived growth factor, a platelet-derived growthfactor analogue, epidermal growth factor, nerve growth factor, acarnitine derivative, uridine, 5-hydroxy-1-methylhydantoin, EGB-761,bimoclomol, sulodexide, Y-128, a hydroxymethyl-glutaryl coenzyme Areductase inhibitor, a fibric acid derivative, a β₃-adrenoceptoragonist, an acyl-coenzyme A: cholesterol acyltransferase inhibitor,probcol, a thyroid hormone receptor agonist, a cholesterol absorptioninhibitor, a lipase inhibitor, a microsomal triglyceride transferprotein inhibitor, a lipoxygenase inhibitor, a carnitinepalmitoyl-transferase inhibitor, a squalene synthase inhibitor, alow-density lipoprotein receptor enhancer, a nicotinic acid derivative,a bile acid sequestrant, a sodium/bile acid cotransporter inhibitor, acholesterol ester transfer protein inhibitor, an appetite suppressant,an angiotensin-converting enzyme inhibitor, a neutral endopeptidaseinhibitor, an angiotensin II receptor antagonist, anendothelin-converting enzyme inhibitor, an endothelin receptorantagonist, a diuretic agent, a calcium antagonist, a vasodilatingantihypertensive agent, a sympathetic blocking agent, a centrally actingantihypertensive agent, an α₂-adrenoceptor agonist, an antiplateletsagent, a uric acid synthesis inhibitor, a uricosuric agent and a urinaryalkalinizer.
 17. A method for the treatment as claimed in claim 5,wherein the disease associated with hyperglycemia is diabetes.
 18. Amethod for the treatment as claimed in claim 5, wherein the diseaseassociated with hyperglycemia is diabetic complications.
 19. A methodfor the treatment as claimed in claim 5, wherein the disease associatedwith hyperglycemia is obesity.
 20. A method for inhibiting a humanSGLT2, which comprises administering an effective amount of anitrogen-containing heterocyclic derivative as claimed in claim 1, or apharmaceutically acceptable salt thereof, or a prodrug thereof.
 21. Amethod for inhibiting a human SGLT2, which comprises administering aneffective amount of a nitrogen-containing heterocyclic derivative asclaimed in claim 2, or a pharmaceutically acceptable salt thereof, or aprodrug thereof.